Complete amide cis-trans switching synchronized with disulfide bond formation and cleavage in a proline-mimicking system.

A typical naturally occurring disulfide structure in proteins is an 8-membered disulfide ring formed between two adjacent cysteine (Cys-Cys) residues. Based on this structure, we designed 7- to 9-membered disulfide ring molecules, embedded in the 7-azabicyclo[2.2.1]heptane skeleton, that switch their conformation from exclusively trans-amide to exclusively cis-amide upon redox transformation from dithiol to disulfide, and vice versa. Constrained shape of disulfide rings is rare in nature, and the present molecular structure is expected to be a useful fundamental component for the construction of new conformation-switching systems.

Comprehensive genetic profiling reveals frequent alterations of driver genes on the X chromosome in extranodal NK/T-cell lymphoma.

Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus (EBV)-related neoplasm with male dominance and a poor prognosis. A better understanding of the genetic alterations and their functional roles in ENKTCL could help improve patient stratification and treatments. Here, we performed comprehensive genetic analysis of 177 ENKTCL cases to delineate the landscape of mutations, copy number alterations (CNAs), and structural variations, identifying 34 driver genes including six previously unappreciated ones, namely HLA-B, HLA-C, ROBO1, CD58, POT1, and MAP2K1. Among them, CD274 (24%) was the most frequently altered, followed by TP53 (20%), CDKN2A (19%), ARID1A (15%), HLA-A (15%), BCOR (14%), and MSN (14%). Chromosome X (chrX) losses were the most common arm-level CNAs in females (~40%), and alterations of four X-linked driver genes (MSN, BCOR, DDX3X, and KDM6A) were more frequent in males and females harboring chrX losses. Among X-linked drivers, MSN was the most recurrently altered, and its expression was lost in approximately one-third of cases using immunohistochemical analysis. Functional studies of human cell lines demonstrated that MSN disruption promoted cell proliferation and NF-κB activation. Moreover, MSN inactivation increased sensitivity to NF-κB inhibition in vitro and in vivo. In addition, recurrent deletions were observed at the origin of replication in the EBV genome (6%). Finally, by integrating the 34 drivers and 19 significant arm-level CNAs, non-negative matrix factorization and consensus clustering identified two molecular groups with different genetic features and prognosis irrespective of clinical prognostic factors. Together, these findings could help improve diagnostic and therapeutic strategies in ENKTCL.

Predictive Postoperative Inflammatory Response Indicators of Infectious Complications Following Gastrectomy for Gastric Cancer.

BACKGROUND: Perioperative factors are useful for predicting postoperative infectious complications (PIC) in gastric cancer. Specifically, postoperative inflammatory response indicators (PIRI), [C-reactive protein (CRP) level, body temperature (BT), and white blood cell (WBC) count], are widely used in clinical practice. We investigated predictive factors for PIC, including PIRI, to establish a simple and practical indicator of postoperative complications after gastrectomy. METHODS: We retrospectively collected clinical data from 200 patients with fStage I-III gastric cancer. Univariate/multivariate analysis was performed to evaluate the relationship of predictive factors [host factors, clinicopathological factors, and PIRI (BT, WBC count, and CRP level on postoperative day (POD) 1 and 3) ]. Cut-off values of the predictive factors were analyzed using receiver operating characteristic (ROC) curve modulated by the presence/absence of PIC Grade II, III (Clavien-Dindo classification). RESULTS: Age [Odds ratio (OR): 5.67], smoking history (OR: 3.51), and CRP level (OR: 5.65), WBC count (OR: 8.96), and BT (OR: 3.37) on POD3 were selected as independent factors from multivariate analysis. Cut-off values were 77 years, 14.8 mg/dL, 116.0×102/µL, and 37.4°C, respectively. CONCLUSIONS: Predictive factors relative to PIC in gastric cancer were CRP level ≥ 14.8 mg/dL, WBC count ≥ 116.0×102/µL, and BT ≥ 37.4°C all on POD3. Age ≥ 77 years, and history of smoking were relative to PIC, suggesting a simple and practical indicator applicable in clinical practice.

Preoperative and Postoperative C-Reactive Protein to Albumin Ratio (CAR) as a Prognostic Marker for Survival of Esophageal Squamous Cell Carcinoma Patients After Surgery.

BACKGROUND/AIM: Recent studies have reported that the C-reactive protein (CRP) to albumin ratio (CAR) may be a useful prognostic biomarker in various types of cancer patients. However, the mechanism underlying this observation is unclear. The present study aimed to clarify why the CAR can predict post-esophagectomy prognosis, the relationship between pre- and postoperative CAR, and whether postoperative CAR can predict the prognosis of esophageal cancer patients. PATIENTS AND METHODS: We investigated 158 esophagectomy patients with esophageal squamous cell carcinoma. Hematological examinations were performed on postoperative days (POD) 1, 3, 5, 7, 10, and 14. RESULTS: Preoperative CAR was a significant independent prognostic factor of overall survival (OS) [hazard ratio (HR)=2.247; p=0.0005], and there was a strong correlation between preoperative CAR and tumor depth. The preoperative high-CAR (pre-high-CAR) group had significantly higher CAR on all postoperative days (POD). We then divided the patients as follows: those with at least two low-CAR days on POD 5, 7, and 10 were assigned to the modified post-low-CAR (mPost-low-CAR) group, and others were assigned to the modified post-high-CAR (mPost-high-CAR) group. The 5-year OS rate was significantly higher in the mPost-low-CAR group than in the mPost-high-CAR group, which predicted a more accurate prognosis (p<0.0001, HR=2.769). CONCLUSION: Preoperative CAR was associated with tumor depth and diameter, and patients in the pre-high-CAR group continued to have significantly higher CAR postoperatively. These factors were presumed to reflect disease prognosis. Furthermore, grouping by CAR on POD 5, 7, and 10 reflected patient prognosis more accurately than preoperative CAR.

The Impact of Pretransplant Use of Tyrosine Kinase Inhibitors on Allogeneic Stem Cell Transplantation in Patients with Chronic Myeloid Leukemia-A Single-institution Retrospective Study.

Objective Chronic myeloid leukemia (CML) is a malignant hematological disorder, and allogeneic stem cell transplantation (allo-SCT) was its only curative treatment until the introduction of tyrosine kinase inhibitors (TKIs). Allo-SCT is still considered for CML patients who are resistant to TKIs and in an advanced phase. Currently, second- and third-generation (2/3 G) TKIs are typically incorporated into the first-line treatment of CML. However, the impact of 2/3 G TKIs on subsequent allo-SCT remains unclear. We therefore evaluated the effect of 2/3 G TKIs on allo-SCT. Methods We retrospectively evaluated the effect of pretransplant therapy with TKIs on the outcome of allo-SCT for CML using clinical data at our institution. Patients or Materials Thirty-two CML patients who received their first allo-SCT procedure at our institute from 2001 to 2020 were included. We divided the patients into three subgroups based on TKI treatment before allo-SCT. Patients receiving no TKIs, only imatinib (IM), and 2/3 G TKIs were classified into the Non-TKI, IM, and 2/3 G TKI groups, respectively. Results In a univariate analysis, the pretransplant use of 2/3 G TKIs was significantly associated with a higher 5-year overall survival (91.7%) and relapse-free survival (75.0%) than the use of IM (37.5% and 12.5%) in patients presenting with or progressing to the advanced phase. In addition, pretransplant use of 2/3 G TKIs did not increase the incidence of graft-versus-host disease (GVHD). Conclusions We demonstrated that the pretransplant use of 2/3 G TKIs was safe and improved the outcome of CML patients who presented with or progressed to the advanced phase without increasing the frequency of GVHD.

Risk factor analysis for cytomegalovirus reactivation under prophylaxis with letermovir after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Letermovir has been approved as a novel cytomegalovirus (CMV) prophylactic agent after allogeneic hematopoietic stem cell transplantation (HSCT). However, there are still insufficient data to properly evaluate the real-world role of letermovir, and the risk factors for CMV reactivation under letermovir prophylaxis have not been clarified. METHODS: We performed a single-institution retrospective analysis of patients under prophylaxis with or without letermovir who underwent allogeneic HSCT between March 2012 and December 2019. In August 2018, letermovir was added to the clinical practice at our institution for the prophylaxis of CMV reactivation in allogeneic HSCT recipients. Patients who underwent HSCT without prophylactic letermovir from March 2012 until September 2018 served as a historical control. RESULTS: The cumulative incidence of clinically significant CMV infection (CS-CMVi) was significantly lower in the letermovir group than in the historical control group not receiving letermovir (30.2% vs. 71.6%, p < .05, at 100 days). In addition, the cumulative incidence of non-relapse mortality (NRM) at day 500 was significantly lower in the letermovir group (4.7% vs. 19.8%, p < .05). We then performed a risk factor analysis for developing CS-CMVi in the letermovir group. The only significant factor identified by this multivariable analysis was transplantation from a CMV seronegative donor to a seropositive recipient (Hazard ratio = 2.76, 95% confidence interval 1.14-6.68, p < .05). CONCLUSION: Our study showed that letermovir prophylaxis significantly reduced the incidence of CS-CMVi and NRM in a real-world setting and that the CMV serostatus of the donor remained as a risk factor for CS-CMVi even under letermovir prophylaxis.

Feasibility of augmented rectangle technique in laparoscopic distal gastrectomy: comparison with hemi-double stapling technique in a single-center retrospective cohort study.

PURPOSE: Augmented rectangle technique (ART) anastomosis is a totally intracorporeal anastomosis of laparoscopic distal gastrectomy (LDG), Billroth I (B1) reconstruction for gastric cancer, which secures a wide anastomotic stoma. Since the conventional extracorporeal hemi-double stapling technique (HD) may have a narrow anastomotic stoma, our aim of this study was to evaluate the feasibility and usefulness of ART anastomosis by comparing the surgical outcomes with HD anastomosis. METHODS: Clinical data of 89 patients undergoing LDG with B1 reconstruction were retrospectively collected. Patients were divided into ART group (n = 40) and HD group (n = 49). Surgical outcomes including short-term outcomes, postoperative endoscopic findings, and nutritional factors 1 year after surgery were compared between the groups. RESULTS: Baseline characteristics were similar between the groups. In terms of short-term outcomes, blood loss was less (11.5 mL vs 40 mL, P = 0.011) and postoperative hospital stay was shorter (10 days vs 12 days, P = 0.022) in the ART group. In terms of endoscopic findings, residual food was less (P = 0.032) in the ART group. In terms of nutritional factors, percent decrease of visceral fat area (- 27.6% vs - 40.5%, P = 0.049) and subcutaneous fat area (- 25.7% vs - 39.3%, P = 0.050) 1 year after surgery attenuated in the ART group. CONCLUSIONS: ART anastomosis is superior in perioperative course such as postoperative hospital stay. Moreover, a better nutritional recovery is expected by securing a wide anastomotic stoma leading to a favorable food passage.

[Genetic studies on lymphoma].

Lymphoma comprises a group of diseases characterized by neoplastic proliferation of mature B, T, and NK cells. This disease entity is widely recognized to be clinically, pathologically, molecularly, and genetically heterogeneous. The classification of lymphomas was classically based on morphology and immunology, but recent dramatic advances in next-generation sequencing technology have revealed various genetic alterations in lymphomas, which influenced the revision of the WHO classification in 2017. Accumulating evidence on genetic alterations has enabled the development of more accurate diagnostic strategies and prognostic markers. Moreover, these findings provide opportunities to exploit new therapeutics that target genetic alterations, which would facilitate the use of precision medicine in lymphomas. Here, we briefly review the fundamental methods of genetic analysis using next-generation sequencing technology and describe the entire scenario of genetic alterations, focusing on the recent major studies that have revealed various genetic alterations in each lymphoma subtype and present a detailed discussion of the results and methods.

First successful case of percutaneous transabdominal thoracic duct embolization (PTTDE) for chylous ascites resulting from laparoscopic gastric cancer surgery.

A 61-year-old woman underwent laparoscopy-assisted distal gastrectomy (LADG) with extragastric lymph node dissection (D2). Two months later, she was readmitted to hospital to be treated for chylous ascites. Oral intake was discontinued and total parenteral nutrition started, but increasing body weight and decreasing serum albumin concentration was not controllable. Percutaneous transabdominal thoracic duct embolization (PTTDE) was performed on the 8th day after the readmission. Five days after PTTDE, oral intake was resumed. Seventeen days after PTTDE, the patient was discharged without recurrence of ascites. She has remained asymptomatic. We describe here the first patient with chylous ascites two months after LADG with D2 dissection for early gastric cancer who was successfully treated by PTTDE.

Synthesis, Structural Characterization, and Optical Properties of Benzene-Fused Tetracyclic and Pentacyclic Stiboles.

The expectation that antimony (Sb) compounds should display phosphorescence emissions based on the "heavy element effect" prompted our interest in the introduction of antimony to a biaryl as the bridging atom in a fused heterole system. Herein, the synthesis, molecular structures, and optical properties of novel benzene-fused heteroacenes containing antimony or arsenic atoms are described. The stiboles and arsole were prepared by the condensation of dibromo(phenyl)stibane or dichloro(phenyl)arsine with dilithium intermediates derived from the corresponding dibromo compounds. Nuclear magnetic resonance (NMR) spectroscopy and X-ray crystal analysis revealed that the linear pentacyclic stibole was highly symmetric in both the solution and crystal states. In contrast, the curved pentacyclic stibole adopted a helical structure in solution, and surprisingly, only M helical molecules were crystallized from the racemate. All synthesized compounds produced very weak or no emissions at room temperature or in the solid state. In contrast, the linear penta- and tetracyclic stiboles exhibited clear phosphorescence emissions in the CHCl3 frozen matrix at 77 K under aerobic conditions.

Synthesis and anticancer activity of bis(2-arylimidazo[1,2-a]pyridin-3-yl) selenides and diselenides: the copper-catalyzed tandem C-H selenation of 2-arylimidazo[1,2-a]pyridine with selenium.

Most heteroaryl selenides and diselenides are biologically active, with some reported to act as antioxidants and show activities that are medicinally relevant; hence, the development of efficient methods for their synthesis is an important objective. Herein, a simple method for the synthesis of selenides and diselenides bearing imidazo[1,2-a]pyridine rings and their anticancer activity are described. The double C-H selenation of imidazo[1,2-a]pyridine with Se powder was catalyzed by CuI (10 mol %) ligated with 1,10-phenanthroline (10 mol %) at 130 °C under aerobic conditions. The selenides or diselenides were prepared almost selectively using selenium powder in an appropriate quantity under otherwise identical reaction conditions. The prepared selenides and diselenides bearing two imidazo[1,2-a]pyridine rings were all novel compounds. Among the prepared diselenides and selenides that exhibited cytotoxicity against cancer cells, bis[2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-3-yl] diselenide showed an excellent anticancer activity and low cytotoxicity toward noncancer cells, suggesting that this diselenide is a potential lead compound for anticancer therapy.

Simultaneous Endoscopic Resection of Superficial Cancers of the Hypopharynx and Esophagus: A Case Report.

Diagnosis and treatment of superficial laryngopharyngeal cancers has recently received considerable attention. Here, we present a case of superficial hypopharyngeal cancer and superficial esophageal cancer treated with simultaneous endoscopic laryngopharyngeal surgery (ELPS) and endoscopic submucosal dissection (ESD). The patient was a 67-year-old man. During his follow-up for distal gastrectomy-performed earlier for stomach cancer-upper gastrointestinal endoscopy revealed three primary cancers: a superficial hypopharyngeal cancer, superficial esophageal cancer, and esophagogastric junction cancer. After total resection of the remnant stomach, combined hypopharyngeal ELPS with esophageal ESD was performed. He developed aspiration pneumonia after surgery but recovered and was discharged on the 16th day. Thus, safe and effective endoscopic therapy can be performed even for double superficial cancers of the laryngopharynx and esophagus.

Clinical characteristics of human herpesvirus-6 myelitis after allogeneic hematopoietic stem cell transplantation and its favorable outcome by early intervention.

After allogeneic hematopoietic stem cell transplantation (HSCT), human herpesvirus-6 (HHV-6) can cause serious central nervous system (CNS) disorder and typically presents as encephalitis. Another manifestation of HHV-6 is myelitis, which has not been fully evaluated. In this study, we retrospectively analyzed 19 patients who developed HHV-6 myelitis after allogeneic HSCT. Median onset was 20 days after transplantation (range, 13-31), with a cumulative incidence of 4.1% at day 40 after transplantation. Median age at transplant was 50 years (range, 17-61). Median copy number of HHV-6 DNA was 3000 copies/ml in cerebrospinal fluid (CSF; range, 200-100,000). The most common symptoms were pruritus, pain of the extremities/back, and numbness. Three patients subsequently developed encephalitis in the clinical course of myelitis; their HHV-6 copy numbers in CSF had been higher than 10,000 copies/ml at the onset of myelitis. Antiviral agents were initiated shortly after onset in all patients, resulting in recovery. These results suggest that myelitis would be an important subtype of HHV-6-associated CNS disorders after allogeneic HSCT, whose prognosis could be favorable by an early intervention. Transplant physicians should recognize early posttransplant neurological symptoms such as pruritus, pain, or numbness as possible signs of HHV-6 myelitis, which could also progress to encephalitis.

Overall Shape Constraint of Alternating α/ß-Hybrid Peptides Containing Bicyclic ß-Proline.

Our NMR, IR/Raman, CD spectroscopic, and X-ray crystallographic studies, as well as accelerated molecular dynamics simulations, showed that alternating hybrid α/ß-peptides containing a bicyclic ß-proline surrogate form unique extended curved folds, regardless of the peptide length and solvent environment. It is suggested that extended ß/PPII structures are preferred in the insulating α-alanine moieties between the rigid bicyclic ß-proline structures. These hybrid peptides inhibit p53-MDM2 and p53-MDMX protein-protein interactions.

Human Herpesvirus 6 Reactivation Evaluated by Digital Polymerase Chain Reaction and Its Association With Dynamics of CD134-Positive T Cells After Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND: Human herpesvirus 6 (HHV-6) causes life-threatening central nervous system disorders after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recent studies implicated CD134 as a specific receptor of HHV-6B and demonstrated that its expression levels in CD4-positive T cells after allo-HSCT could be related to the reactivation of HHV-6. We prospectively evaluated the relationship between HHV-6 reactivation and CD134+ T cells in the recipients of allo-HSCT. METHODS: HHV-6 viral load in plasma was quantitatively measured weekly after allo-HSCT by digital polymerase chain reaction in 34 patients. The ratio of CD134 in CD4+ T cells (CD134/CD4 ratio) was serially measured by flow cytometry before and after transplantation. RESULTS: HHV-6 reactivation was detected in 23 patients (68%). The CD134/CD4 ratio before conditioning was significantly higher in patients with HHV-6 reactivation than in those without (median, 3.8% vs 1.5%, P < .01). In multivariate analysis, a higher CD134/CD4 ratio before conditioning was significantly associated with the incidence of HHV-6 reactivation (odds ratio, 10.5 [95% confidence interval, 1.3-85.1], P = .03). CONCLUSIONS: A higher CD134/CD4 ratio before conditioning was associated with a higher risk of HHV-6 reactivation, suggesting that the rate may be a promising marker for predicting HHV-6 reactivation after allo-HSCT.

Postoperative Pneumonia After Esophagectomy and Systemic Inflammatory Response Syndrome.

BACKGROUND/AIM: The aim of this study was to determine the association between post-esophagectomy pneumonia and the presence of pathogenic organisms in the sputum or pharynx and postoperative systemic inflammatory response syndrome (SIRS). MATERIALS AND METHODS: This retrospective study included 98 patients diagnosed with esophageal cancer who had undergone esophagectomy. RESULTS: Postoperative pneumonia was observed in 24 patients (24.5%). Of the total 98 patients, 45 (45.9%) were tested positive for pathogenic organisms preoperatively, and 16 of those (35.6%) developed postoperative pneumonia; postoperative pneumonia occurred at a higher rate in these patients compared to pathogenic organism-negative patients (p=0.019). Postoperative SIRS was observed in 62 patients (63.3%), and 21 of these (33.9%) developed postoperative pneumonia, a significantly higher rate compared to patients without SIRS (p=0.007). CONCLUSION: Postoperative pneumonia was significantly associated with the presence of pathogenic organisms in the sputum or pharynx and postoperative SIRS.

[A Case of Rectal Obstruction Due to Gastric Cancer Dissemination for Which Rectal Stenting Was Performed Twice].

Malignant colorectal obstruction results in a worse quality of life and makes it difficult for patients to continue chemotherapy. In this paper, we present a case of rectal obstruction caused by gastric cancer dissemination for which rectal stent insertions were performed twice. The patient was a 72-year-old woman. She underwent gastrectomy for Stage Ⅳ gastric cancer (ypT3, N1, M1, P0, H0, CY+). Twenty-eight months after gastrectomy, she experienced rectal obstruction due to peritoneal dissemination. A rectal stent was placed at the stenosis site. She was administered chemotherapy after stenting. Seven months later, she developed rectal obstruction due to tumor in-growth. Rectal stenting was performed again. Subsequently, the patient had no abdominal symptoms until she died, 2 months after the second stenting.

Eight ent-Kaurane Diterpenoid Glycosides Named Diosmariosides A-H from the Leaves of Diospyros maritima and Their Cytotoxic Activity.

From the leaves of Diospyros maritima, collected from Okinawa Island, eight new glycosides based on ent-kaurane-type diterpenoids, entitled diosmariosides A-H, were isolated. The absolute structure of diosmarioside E (5) was determined by X-ray crystallographic analysis. The structure of diosmarioside H was elucidated to be a dimeric compound between diosmarioside A and a sugeroside through a ketal bond. An assay of cytotoxicity towards the lung adenocarcinoma (A549) cell line was performed. Among the compounds isolated, only diosmarioside D (4) and sugeroside 9 showed strong activity. The anti-microbial activity toward multi-drug resistant strains was also determined, but no activity was observed.