Decreased Paneth cell α-defensins promote fibrosis in a choline-deficient L-amino acid-defined high-fat diet-induced mouse model of nonalcoholic steatohepatitis via disrupting intestinal microbiota.

Nonalcoholic steatohepatitis (NASH) is a chronic liver disease characterized by fibrosis that develops from fatty liver. Disruption of intestinal microbiota homeostasis, dysbiosis, is associated with fibrosis development in NASH. An antimicrobial peptide α-defensin secreted by Paneth cells in the small intestine is known to regulate composition of the intestinal microbiota. However, involvement of α-defensin in NASH remains unknown. Here, we show that in diet-induced NASH model mice, decrease of fecal α-defensin along with dysbiosis occurs before NASH onset. When α-defensin levels in the intestinal lumen are restored by intravenous administration of R-Spondin1 to induce Paneth cell regeneration or by oral administration of α-defensins, liver fibrosis is ameliorated with dissolving dysbiosis. Furthermore, R-Spondin1 and α-defensin improved liver pathologies together with different features in the intestinal microbiota. These results indicate that decreased α-defensin secretion induces liver fibrosis through dysbiosis, further suggesting Paneth cell α-defensin as a potential therapeutic target for NASH.

Control of intramolecular singlet fission in a pentacene dimer by hydrostatic pressure.

Singlet fission (SF), which produces two triplet excitons from a singlet exciton, has been identified as a novel nanointerface for efficient (photo)energy conversion. This study aims to control exciton formation in a pentacene dimer through intramolecular SF using hydrostatic pressure as an external stimulus. We reveal the hydrostatic-pressure-induced formation and dissociation processes of correlated triplet pairs (TT) in SF by means of pressure-dependent UV/vis and fluorescence spectrometry and fluorescence lifetime and nanosecond transient absorption measurements. The photophysical properties obtained under hydrostatic pressure suggested distinct acceleration of the SF dynamics by microenvironmental desolvation, the volumetric compaction of the TT intermediate based on solvent reorientation toward an individual triplet (T1), and pressure-induced shortening of T1 lifetimes. This study provides a new perspective on the control of SF by hydrostatic pressure as an attractive alternative to the conventional control strategy for SF-based materials.

Molecular Mechanism of Spectral Tuning by Chloride Binding in Monkey Green Sensitive Visual Pigment.

The visual pigments of the cones perceive red, green, and blue colors. The monkey green (MG) pigment possesses a unique Cl- binding site; however, its relationship to the spectral tuning in green pigments remains elusive. Recently, FTIR spectroscopy revealed the characteristic structural modifications of the retinal binding site by Cl- binding. Herein, we report the computational structural modeling of MG pigments and quantum-chemical simulation to investigate its spectral redshift and physicochemical relevance when Cl- is present. Our protein structures reflect the previously suggested structural changes. AlphaFold2 failed to predict these structural changes. Excited-state calculations successfully reproduced the experimental red-shifted absorption energies, corroborating our protein structures. Electrostatic energy decomposition revealed that the redshift results from the His197 protonation state and conformations of Glu129, Ser202, and Ala308; however, Cl- itself contributes to the blueshift. Site-directed mutagenesis supported our analysis. These modeled structures may provide a valuable foundation for studying cone pigments.

Thermodynamic Control of Intramolecular Singlet Fission and Exciton Transport in Linear Tetracene Oligomers.

We newly synthesized a series of homo- and hetero-tetracene (Tc) oligomers to propose a molecular design strategy for the efficient exciton transport in linear oligomers by promoting correlated triplet pair (TT) dissociation and controlling sequential exciton trapping process of individual doubled triplet excitons (T+T) by intramolecular singlet fission. First, entropic gain effects on the number of Tc units are examined by comparing Tc-homo-oligomers [(Tc)n : n=2, 4, 6]. Then, a comparison of (Tc)n and Tc-hetero-oligomer [TcF3 -(Tc)4 -TcF3 ] reveals the vibronic coupling effect for entropic gain. Observed entropic effects on the T+T formation indicated that the exciton migration is rationalized by number of possible TT states increased both by increasing the number of Tc units and by the vibronic levels at the terminal TcF3 units. Finally, we successfully observed high-yield exciton trapping process (trapped triplet yield: ΦTrT =176 %).

[A Case of Intussusception Caused by Ascending Colon Cancer That Underwent Elective Surgery without Repositioning].

An 81-year-old man visited his previous doctor with complaints of fever, vomiting, and diarrhea, and was transferred to our hospital on the 8th day after being admitted to the hospital for further treatment for a mass in the right side of his abdomen on CT. At the time of transfer, a fist-sized mass was palpable in the right side of the abdomen, but there was no tenderness, and blood tests showed that the white blood cell count was 10,700/µL and CRP 1.36 mg/dL, indicating a mild increase in inflammatory reaction. Contrast-enhanced CT showed an 8-cm diameter mass in the ascending colon with a stratified structure, and an antegrade intussusception with the mass as the advanced part. No intestinal obstruction was showed, and the contrast effect on the wall of the intestinal wall of the intussusception was favorable. Since the intussusception was already present on the previous CT scan, and since the patient also had severe aortic stenosis and a cardiothoracic examination was necessary, we decided on an elective operation. During the waiting period, lower gastrointestinal endoscopy revealed a type 1 tumor in the ascending colon, and biopsy revealed a highly differentiated tubular adenocarcinoma. The scope was not passed through to the oral side, and endoscopic repositioning was difficult. On the 19th day(12th day of admission), right hemicolectomy of the colon with D3 lymphadenectomy was performed. Since the descending duodenal wall was partially retracted into the area of the duplication, a partial resection of the duodenal wall was also performed, and the specimen was removed without releasing the duplication. Histopathologically, the tumor was diagnosed a 9.5×5.7 cm type 1 tumor with pT3, pN0, cM0, pStage Ⅱa(9th edition). The patient was discharged on the 9th postoperative day with good postoperative course.

[A Case of Ascending Colon Cancer with a Tumor Thrombus in the Superior Mesenteric Vein].

The progression of intravenous tumor thrombus in colorectal cancer is rare and reports on its resection are limited. This study reports a case of ascending colon cancer with a tumor thrombus in the superior mesenteric vein(SMV). A 44-year-old woman was admitted to our hospital for right, lower abdominal pain. Dynamic CT revealed an enhanced mass in the ascending colon and a tumor thrombus in the SMV. She was diagnosed with ascending colon cancer and an SMV tumor thrombus. An extended right hemicolectomy was performed. The SMV tumor thrombus extended from the gastrocolic trunk (GCT)to the right gastroepiploic vein and the anterior superior pancreaticoduodenal vein. To remove the tumor thrombus, a wedge-shaped incision was made through the SMV. Pathological examination showed a moderately differentiated adenocarcinoma of the ascending colon with extra-regional lymph node metastasis(No. 6)and intrapancreatic venous invasion. The pathological staging was pT4b, pN0, pM1a, pStage Ⅳa(Japanese Classification 9th edition). The patient was discharged on day 13 postoperatively. After discharge, 14 courses of mFOLFOX6 plus bevacizumab chemotherapy were administered. The patient is currently alive with no recurrence 15 months postoperatively.

Enthalpy-Entropy Compensation Effect for Triplet Pair Dissociation of Intramolecular Singlet Fission in Phenylene Spacer-Bridged Hexacene Dimers.

Hexacene (Hc) is highly promising for singlet fission (SF). However, the number of SFs in Hc is extremely limited. As far as Hc dimers in solution are concerned, there is no report on the observation of the dissociation process from a correlated triplet pair (TT) to an individual one. The emphasis in this study is on the first observation of the quantitative TT generation together with the orientation-dependent photophysical discussions for TT dissociation using para- and meta-phenyl-bridged Hc dimers. Moreover, the activation enthalpies of Hc dimers in TT dissociation are smaller than those of pentacene (Pc) dimers, whereas the relative entropic contributions for Gibbs free energy of activation are much larger than the enthalpic ones in both Hc and Pc dimers. This implies that the vibrational motions are responsible for the intramolecular conformation changes associated with the TT dissociation. Consequently, "enthalpy-entropy compensation" has a large impact on the rate constants and quantum yields.

[A Resected Case of Intussusception Due to Undifferentiated Carcinoma of the Colon].

An 89-year-old woman was pointed out to have anemia for a routine blood examination by her family doctor and was referred to our gastroenterological department for further examination. Colonoscopy showed a type Ⅰ tumor in the transverse colon and insertion of fiber across the tumor was difficult. On contrast enema using gastrographin, a crab's claw-like appearance was found. CT after contrast enema revealed a tumor, 5 cm in diameter with pseudokidney sign near the hepatic flexure of the transverse colon. Pathological examination of biopsy specimen proved the tumor to be a poorly differentiated adenocarcinoma. Thus, she was diagnosed with intussusception due to transverse colon cancer and we performed partial resection of the transverse colon without regional lymphadenectomy. Final pathological diagnosis of the tumor was undifferentiated carcinoma and tumor stage was pT3pN0cM0, pStage Ⅱa. She was discharged 13 days after surgery and alive without tumor recurrence at 7 months after surgery, not undergoing adjuvant chemotherapy.

[A Case of Conversion Surgery following Chemotherapy for HER2-Positive Advanced Gastric Cancer].

A 73-year-old female was referred to the gastroenterological department of our hospital for examination because of anemia. CA19-9 increased to 1,392 U/mL, and upper endoscopy revealed type 2 gastric cancer extending from the anterior wall to the lesser curvature in the lower part of the gastric body. Biopsy specimens revealed well-differentiated tubular adenocarcinoma, and HER2 was positive immunohistologically. Contrast-enhanced CT revealed wall thickness of the lower part of the gastric body with marked lymph node swelling beside the lesser curvature and a low-density nodule measuring 10 mm in diameter with rim enhancement in segment 5 of the liver, indicative of liver metastasis. Thus, she was diagnosed with unresectable advanced gastric cancer(cT3cN2M1, HEP, cStage ⅣB), and combined chemotherapy with capecitabine, cisplatin, and trastuzumab was administered. After 7 courses, CA19-9 normalized, and upper endoscopy revealed a scar of the primary tumor, and cancer was not detected in the biopsy specimen. On contrast-enhanced CT, lymph nodes beside the lesser curvature shrank significantly, and liver nodules disappeared. She was referred to our department for conversion surgery, and distal gastrectomy with D2 lymph node dissection was performed 7 months after her first visit to our hospital. Pathologically, tumor invasion was restricted to the lamina propria, and lymph node metastasis was not observed(ypT1aN0M0, ypStage Ⅰ A). She was discharged on postoperative day 13 and is alive without tumor recurrence at 7 months after surgery. She is not currently undergoing adjuvant chemotherapy.

Geometries and Terahertz Motions Driving Quintet Multiexcitons and Ultimate Triplet-Triplet Dissociations via the Intramolecular Singlet Fissions.

Importance of vibronic effects has been highlighted for the singlet-fission (SF) that converts one high-energy singlet exciton into doubled triplet excitons, as strongly coupled multiexcitons. However, molecular mechanisms of spin conversion processes and ultimate decouplings in the multiexcitons are poorly understood. We have analyzed geometries and exchange couplings (singlet-quintet energy gaps: 6J) of the photoinduced multiexcitons in the pentacene dimers bridged by a phenylene at ortho and meta positions [denoted as o-(Pc)2 and m-(Pc)2] by simulations of the time-resolved electron paramagnetic resonance spectra. We clarified that terahertz molecular conformation dynamics play roles on the spin conversion from the singlet strongly coupled multiexcitons 1(TT) to the quintet multiexcitons 5(TT) and on the intramolecular decouplings in the 6J to form spin correlated triplet pairs (T+T). The strongly coupled 5(TT) multiexcitons are revealed to possess entirely planar conformations stabilized by mutually delocalized spin distributions, while the intramolecular decoupled spin-correlated triplet pairs generated at 1 µs are also stabilized by distorted conformations resulting in two separately localized biradical characters.

[Case of Resected Retroperitoneal Dedifferentiated Liposarcoma Extending to the Posterior Mediastinum].

A 71-year-old woman visited our hospital for the examination and treatment of retroperitoneal tumor. CT showed a retroperitoneal tumor extending to the posterior mediastinum; the tumor pressed the IVC and widely abutted the aorta. On MRI, the tumor showed low intensity on T1WI and high intensity on T2WI and DWI. However, the tumor did not show signal reduction on an ADC map. PET-CT showed high accumulation at the tumor. The patient was diagnosed with sarcoma arising from the retroperitoneum. The tumor located on a part of the diaphragm was resected. Histological examination revealed spindle cells with atypical nuclear and multinuclear cells. There were no lesions of well-differentiated liposarcoma. Both CDK4 and MDM2 tested positive on immunohistological staining. Histopathologically, the tumor was diagnosed as dedifferentiated liposarcoma without any well-differentiated liposarcoma component. The postoperative course was uneventful, and she was discharged on the 13th day after surgery. Two months after surgery, no recurrence has been detected.

Paneth cell α-defensin misfolding correlates with dysbiosis and ileitis in Crohn's disease model mice.

Crohn's disease (CD) is an intractable inflammatory bowel disease, and dysbiosis, disruption of the intestinal microbiota, is associated with CD pathophysiology. ER stress, disruption of ER homeostasis in Paneth cells of the small intestine, and α-defensin misfolding have been reported in CD patients. Because α-defensins regulate the composition of the intestinal microbiota, their misfolding may cause dysbiosis. However, whether ER stress, α-defensin misfolding, and dysbiosis contribute to the pathophysiology of CD remains unknown. Here, we show that abnormal Paneth cells with markers of ER stress appear in SAMP1/YitFc, a mouse model of CD, along with disease progression. Those mice secrete reduced-form α-defensins that lack disulfide bonds into the intestinal lumen, a condition not found in normal mice, and reduced-form α-defensins correlate with dysbiosis during disease progression. Moreover, administration of reduced-form α-defensins to wild-type mice induces the dysbiosis. These data provide novel insights into CD pathogenesis induced by dysbiosis resulting from Paneth cell α-defensin misfolding and they suggest further that Paneth cells may be potential therapeutic targets.

[Two Cases of Gastric Cancer Diagnosed after Omental Patch Repair for Gastric Perforation].

Case 1: A 62-year-old man was urgently admitted to our hospital because of left lower abdominal pain. Abdominal CT showed gastric perforation and we performed omental patch repair emergently. Postoperative upper gastrointestinal endoscope revealed an ulcerative lesion in the lesser curve of upper area of gastric body, which proved to be a poorly differentiated adenocarcinoma by biopsy. Thus, we performed total gastrectomy with D2 lymph node dissection. Resected specimen revealed type 2 gastric cancer in the perforated area. Pathological stage was pT3pN0M0, pStage ⅡA. Adjuvant chemotherapy by S-1 was performed and he is alive without tumor recurrence 12 months after the first operation. Case 2: A 71-year- old man was urgently admitted to our hospital because of upper abdominal pain after dinner. Abdominal CT suggested gastric perforation and we performed emergent laparoscopic operation. Perforated lesion about 8 mm in diameter was found in the anterior wall of gastric body. After debridement, perforated lesion was closed with a running suture and additionally omental patch repair was performed. Pathologically, well-differentiated adenocarcinoma was detected in the debridement tissue, and he was diagnosed with perforated gastric cancer. Thus, we performed total gastrectomy with D2 lymph node dissection 28 days after surgery. Pathological stage was pT3pN0M0, pStage ⅡA. Adjuvant chemotherapy by CapeOX was performed and he is alive without tumor recurrence 12 months after the first operation.

[Resected Cases of Primary Duodenal Carcinoma-A Ten-Year Experience].

Primary duodenal carcinoma excluding tumors of the ampulla of Vaterare are rare, thus, therapeutic strategy has not been established. In this study, we investigated the treatment outcome of 7 cases of duodenal carcinoma resected in our hospital between January 2010 and December 2019. The tumor locations were the duodenal bulb in 5(71%), the descending part and the transverse part in 1, respectively. Distal gastrectomy was performed in 4 out of 5 bulbous cases, and pancreatoduodenectomy was performed in the other 3 cases. The pathological stage by the 8th edition of the UICC TNM classification was Stage Ⅰ(T1a/T2, N0)in 3 cases, ⅡA(T3, N0)in 1, ⅢA(N1)in 2, and ⅢB(N2)in 1. R0 resection was achieved in all cases. Adjuvant chemotherapy with S-1 was performed in 3 of 4 patients with Stage Ⅱ or more advanced Stage. There were no tumor recurrences in 4 patients with Stage Ⅰ and Stage ⅡA, but recurrence was occurred in 2 of 3 patients with Stage ⅢA or more. The surgical outcome for duodenal carcinoma without lymph node metastasis were good. On the other hand, the prognosis for advanced cases with lymph node metastasis were poor. Thus, the development of effective adjuvant chemotherapy is strongly expected.

Role of Gln114 in Spectral Tuning of a Long-Wavelength Sensitive Visual Pigment.

Visual pigments of the long-wavelength sensitive opsin group (L group) are anion sensitive in nature. Their highly conserved amino acid residues, H197 and K200, exclusively interact with a chloride ion (Cl-) in the chromophore-binding pocket. Substitution of H197 completely abolishes Cl- binding and results in an ∼30 nm spectral blue-shift. Recent attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy studies of monkey green sensitive pigment have provided insights into the role of Cl- binding in stabilizing the antiparallel ß-sheet at extracellular loop 2 (ECL2). In addition to maintaining the dark state of L opsins, Cl- binding is also believed to play a crucial role in spectral tuning. Here, we used a combination of site-directed mutagenesis in combination with UV-visible spectroscopy to show that Q1142.65 that is positioned far from ECL2 is also a crucial residue for the Cl- effect in L opsins. Comprehensive FTIR spectroscopic analyses on both ion-binding-induced and light-induced structural changes revealed that Q1142.65 contributes to the stability of ß-sheet structure indirectly even though Q1142.65 is not located in ECL2. Overall, these structure-function studies are important for understanding the functional role of Cl- binding in L opsins.

[Two Cases of Complete Response to Trastuzumab Combined with Chemotherapy for Recurrence of HER2-Positive Gastric Cancer].

Case 1: A 67-year-old male underwent distal gastrectomy for advanced gastric cancer. Postoperative histopathological examination indicated pT2a, pN2, M0, pStage ⅢA. He received 4 courses of TS-1 with paclitaxel chemotherapy and TS-1 chemotherapy for 2 years. Three years and 5 months after surgery, computed tomography suggested lymph node metastasis of the mediastinum, so TS-1 with cisplatin(CDDP)therapy was administered. Five years and 10 months after surgery, recurrence occurred and docetaxel and CPT-11 were administered with no response. Since HER2 was overexpressed in the primary tumor, he was treated with capecitabine, CDDP, and trastuzumab(XPT)therapy. After 1 year and 6 months, the patient was considered to have achieved a complete response(CR), and after further trastuzumab therapy for half a year, CR was maintained for 12 years and 3 months after surgery. Case 2: A 59-year-old female underwent total gastrectomy for advanced gastric cancer. Postoperative histopathological examination indicated pT3, pN3a, M0, pStageⅢB. She received TS-1 chemotherapy for 1 year and 8 months. Computed tomography suggested paraaortic lymph node metastasis, and XPT therapy was administered. The patients responded well, and alternate administration of XPT and capecitabine and docetaxel(XT) was performed. Three years and 5 months after surgery, recurrence of lymphadenopathy occurred and intensity-modulated radiation therapy in addition to XPT/XT alternate therapy was introduced, leading to a CR 5 years and 8months after surgery. XT therapy was continued afterward, and CR was maintained for 9 years and 2 months after surgery.

Multiexciton Dynamics Depending on Intramolecular Orientations in Pentacene Dimers: Recombination and Dissociation of Correlated Triplet Pairs.

Pentacene dimers bridged by a phenylene at ortho and meta positions [denoted as o-(Pc)2 and m-(Pc)2] were synthesized to examine intramolecular orientation-dependent multiexciton dynamics, especially focusing on singlet fission (SF) and recombination from correlated triplet pairs [(TT)]. Absorption and electrochemical measurements indicated strong intramolecular couplings of o-(Pc)2 relative to m-(Pc)2. Femtosecond and nanosecond TA measurements successfully demonstrated efficient SF in both dimers. In contrast, the dissociation process from the (TT) to the individual triplets [(2 × T)] was clearly observed in m-(Pc)2, which is in sharp contrast to a major recombination process in o-(Pc)2. Time-resolved electron spin resonance (TR-ESR) measurements demonstrated that the recombination and dissociation proceed from the quintet state of 5(TT) in m-(Pc)2. The rate constant of the SF was 2 orders of magnitude greater in o-(Pc)2 than that in m-(Pc)2 and was rationalized by enhanced electronic coupling between adjacent HOMOs of the Pc units.

Successful diagnosis of type II enteropathy-associated T-cell lymphoma using flow cytometry and the cell block technique of celomic fluid manifesting as massive pyoid ascites that could not be diagnosed via emergency laparotomy.

Enteropathy-associated T-cell lymphoma (EATL), an intestinal tumor of intraepithelial T lymphocytes, is a rare and highly aggressive disease. We herein describe a case of type II EATL with massive pyoid ascites in which a histological examination could not be performed despite emergency laparotomy that was successfully diagnosed using flow cytometry and the cell block technique to analyze the celomic fluid. This case suggests that EATL should be included in the differential diagnosis of pyoid ascites of unknown origin and that flow cytometry and the cell block technique of assessing celomic fluid are useful procedures for diagnosing EATL, especially in cases in which conducting a histological examination is impossible.

Ectopic ileal varices associated with recurrent bleeding: report of a case.

Bleeding from ectopic varices of the ileum associated with portal hypertension is occasionally life-threatening. However, it is not easy to make an accurate preoperative diagnosis. A 62-year-old woman presented with hematochezia and anemia. Conventional examinations could not locate the bleeding point, but subsequent capsule endoscopy indicated gastrointestinal bleeding from hemorrhaging ileal varices. Contrast-enhanced abdominal computed tomography, three-dimensioned abdominal computed tomography, and mesenteric angiography demonstrated the presence of ileal and right ovarian varices. The patient then underwent an exploratory laparotomy which confirmed these findings, and resection of the affected ileum and right ovary was performed safely. Capsule endoscopy should be a diagnostic option for patients with obscure gastrointestinal bleeding, and ileal varices should be considered as one of the differential diagnoses.

Intralobar pulmonary sequestration associated with marked elevation of serum carbohydrate antigen 19-9.

This report describes a 62-year-old man who experienced elevated serum carbohydrate antigen 19-9 (CA19-9) levels (>500 U/mL) for 4 years, and was finally diagnosed with right intralobar pulmonary sequestration. Surgery confirmed the presence an aberrant artery arising from the descending thoracic aorta and entering the right lower lobe basal segment. Immunohistochemistry demonstrated markedly positive staining of CA19-9 in the ciliated cylindrical epithelia, alveoli, and mucus in the cysts. After pulmonary resection, CA19-9 levels decreased to within a normal range. Therefore, the cause of the elevated serum CA19-9 levels in this case was almost certainly due to intralobar pulmonary sequestration.