Identification of a unique subset of tissue-resident memory CD4+ T cells in Crohn's disease.

T cells differentiate into highly diverse subsets and display plasticity depending on the environment. Although lymphocytes are key mediators of inflammation, functional specialization of T cells in inflammatory bowel disease (IBD) has not been effectively described. Here, we performed deep profiling of T cells in the intestinal mucosa of IBD and identified a CD4+ tissue-resident memory T cell (Trm) subset that is increased in Crohn's disease (CD) showing unique inflammatory properties. Functionally and transcriptionally distinct CD4+ Trm subsets are observed in the inflamed gut mucosa, among which a CD-specific CD4+ Trm subset, expressing CD161 and CCR5 along with CD103, displays previously unrecognized pleiotropic signatures of innate and effector activities. These inflammatory features are further enhanced by their spatial proximity to gut epithelial cells. Furthermore, the CD-specific CD4+ Trm subset is the most predominant producer of type 1 inflammatory cytokines upon various stimulations among all CD4+ T cells, suggesting that the accumulation of this T cell subset is a pathological hallmark of CD. Our results provide comprehensive insights into the pathogenesis of IBD, paving the way for decoding of the molecular mechanisms underlying this disease.

Jasmonate inhibits plant growth and reduces gibberellin levels via microRNA5998 and transcription factor MYC2.

Jasmonate (JA) and gibberellins (GAs) exert antagonistic effects on plant growth and development in response to environmental and endogenous stimuli. Although the crosstalk between JA and GA has been elucidated, the role of JA in GA biosynthesis remains unclear. Therefore, in this study, we investigated the mechanism underlying JA-mediated regulation of endogenous GA levels in Arabidopsis (Arabidopsis thaliana). Transient and electrophoretic mobility shift assays showed that transcription factor MYC2 regulates GA inactivation genes. Using transgenic plants, we further evaluated the contribution of MYC2 in regulating GA inactivation genes. JA treatment increased DELLA accumulation but did not inhibit DELLA protein degradation. Additionally, JA treatment decreased bioactive GA content, including GA4, significantly decreased the expression of GA biosynthesis genes, including ent-kaurene synthase (AtKS), GA 3ß-hydroxylase (AtGA3ox1), and AtGA3ox2, and increased the expression of GA inactivation genes, including GA 2 oxidase (AtGA2ox4), AtGA2ox7, and AtGA2ox9. Conversely, JA treatment did not significantly affect gene expression in the myc2 myc3 myc4 triple mutant, demonstrating the MYC2-4-dependent effects of JA in GA biosynthesis. Additionally, JA post-transcriptionally regulated AtGA3ox1 expression. We identified microRNA miR5998 as an AtGA3ox1-associated miRNA; its overexpression inhibited plant growth by suppressing AtGA3ox1 expression. Overall, our findings indicate that JA treatment inhibits endogenous GA levels and plant growth by decreasing the expression of GA biosynthesis genes and increasing the expression of GA inactivation genes via miR5998 and MYC2 activities.

Loss of PWT7, Located on a Supernumerary Chromosome, Is Associated with Parasitic Specialization of Pyricularia oryzae on Wheat.

Pyricularia oryzae, a blast fungus of gramineous plants, is composed of various host genus-specific pathotypes. The avirulence of an Avena isolate on wheat is conditioned by PWT3 and PWT4. We isolated the third avirulence gene from the Avena isolate and designated it as PWT7. PWT7 was effective as an avirulence gene only at the seedling stage or on leaves. PWT7 homologs were widely distributed in a subpopulation of the Eleusine pathotype and the Lolium pathotype but completely absent in the Triticum pathotype (the wheat blast fungus). The PWT7 homolog found in the Eleusine pathotype was one of the five genes involved in its avirulence on wheat. A comparative analysis of distribution of PWT7 and the other two genes previously identified in the Eleusine pathotype suggested that, in the course of parasitic specialization toward the wheat blast fungus, a common ancestor of the Eleusine, Lolium, Avena, and Triticum pathotypes first lost PWT6, secondly PWT7, and, finally, the function of PWT3. PWT7 or its homologs were located on core chromosomes in Setaria and Eleusine isolates but on supernumerary chromosomes in Lolium and Avena isolates. This is an example of interchromosomal translocations of effector genes between core and supernumerary chromosomes. [Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Epidemiology and molecular characterization of fecal carriage of third-generation cephalosporin-resistant Enterobacterales among elderly residents in Japan.

INTRODUCTION: The spread of third-generation cephalosporin-resistant Gram-negative bacteria is a serious concern in acute and post-acute care settings. This study aimed to understand the epidemiology and molecular background of fecal colonization of resistant Enterobacterales in elderly people. METHODS: In December 2015-December 2017, stool or rectal swab samples were collected from 101 elderly patients receiving home care, using long-term care facilities (LTCF), and living in nursing homes repeatedly at 3-9-month intervals. Patient clinical background data were collected from medical records. After phenotypic screening for extended-spectrum ß-lactamase (ESBL), AmpC-type ß-lactamase or carbapenemase production, drug resistance genes of isolates were analyzed using polymerase chain reaction (PCR). ESBL-producing Escherichia coli isolates obtained from the same patients in repetitive screenings were analyzed using PCR-based ORF typing. Risk factors for persistent carriage of resistant Enterobacterales were analyzed using multivariate analysis. RESULTS: Resistant Enterobacterales isolates were detected in 37 of 101 (36.6%) and 29 of 80 (36.3%) residents in first and second screenings, respectively. ESBL-producing E. coli accounted for 80% isolates, the most common being CTX-M-9-group ß-lactamase producers. Molecular epidemiological analysis revealed probable transmissions of ESBL-producing E. coli; 58% of ESBL-producing E. coli colonizers were persistent colonizers at least after 3 -month intervals. Age > 87 years and LTCF residence were independent risk factors for persistent carriage of ESBL-producing E. coli. CONCLUSIONS: We showed, for the first time, high persistent colonization rate of ESBL-producing E. coli among elderly people in post-acute care settings with probable horizontal transmission. We also identified significant risk factors for persistent colonization.

Locally advanced rectal cancer receiving total neoadjuvant therapy combined with nivolumab: a case report and literature review.

BACKGROUND: The standard treatment for locally advanced rectal cancer (LARC) is preoperative chemoradiotherapy (CRT) followed by surgery and adjuvant chemotherapy. However, it has been suggested that intensification of neoadjuvant treatment with polychemotherapy in addition to CRT instead of as an adjuvant chemotherapy is better tolerated and associated with a higher pathological complete response (pCR) rate. This concept is known as total neoadjuvant therapy (TNT). Recently, the addition of immunotherapy to preoperative CRT has been reported to be useful in LARC patients with mismatch-repair-deficiency and high levels of microsatellite instability (MSI-H), but there are no reports showing the therapeutic effect of nivolumab in combination with TNT. CASE PRESENTATION: A 23-year-old man had frequent diarrhea. Preoperative examination revealed two adenocarcinomas in the rectum. His maternal grandmother had a rectal cancer patient who developed the disease at age 70s. The larger tumor was located at the peritoneal reflection, and its anterior border close to the prostate (<1 mm); there were eight enlarged pararectal lymph nodes. Considering the size and depth of the tumor, it was judged that radical resection with sufficient margins would be difficult. Therefore, it was decided that TNT would be performed. At first, CAPOX (capecitabine and L-OHP) was administered, followed by preoperative CRT (RT:50.4 Gy and capecitabine). During this period, genetic testing diagnosed this patient as MSI-H, so additional nivolumab was administered after CRT. Colonoscopy revealed that the larger tumor was no longer detectable, so robot-assisted intersphincteric resection and bilateral lateral lymph node dissection was performed. The diagnosis of pCR was made for the larger tumor and partial response was achieved for the smaller tumor, and no lymph node metastasis was found. Major complications were not observed and the patient was discharged on the 14th day after surgery. He was followed up without adjuvant chemotherapy and is alive and recurrence-free after 9 months. CONCLUSION: A case of LARC with MSI-H was treated with TNT with nivolumab, resulting in pCR and complete radical resection. This result suggests that nivolumab in addition to TNT can be an option as a preoperative strategy for LARC with MSI-H.

The prediction of postoperative anorectal dysfunction after low anterior resection for lower rectal cancer by measuring the volume of defecation-related muscles.

PURPOSE: Approximately 90% of patients are thought to develop bowel dysfunction after low anterior resection (LAR). Although some prognostic factors have been reported, the volumes of defecation-related muscles have not been examined. This retrospective study investigated the association between the preoperative volume of defecation-related muscles and major LARS. METHODS: Forty-six patients who underwent LAR for rectal cancer between 2013 and 2020 in our institution were analyzed. They had no local residual tumor or local recurrence at the time of the study and no problems with their defecation function pre-operatively. Defecation-related muscle volume measurements were made before surgery, and the patients answered a low anterior resection syndrome (LARS) score questionnaire after surgery. The muscle volume was adjusted by the patient's height squared. RESULTS: Twenty-seven patients (58.7%) developed major LARS. In the univariate analysis, sex, lateral lymph node dissection, and diverting ileostomy as well as muscle volume of the external anal sphincter, pubococcygeal + iliococcygeus muscle, and puborectal muscle were associated with major LARS. In a multivariate analysis, pubococcygeal + iliococcygeus muscle (< 5.96 ml/m2) was the only factor (p = 0.02). CONCLUSIONS: Measuring the volume of the defecation-related muscles may aid in predicting major LARS.

[A Case of Robot-Assisted Abdominoperineal Resection for Local Control for Lower Rectal Cancer with Synchronous Liver and Lung Metastases].

The patient was a 70s woman who was referred to our hospital with a complaint of bloody stool. Colonoscopy revealed type 2 tumor at a distance of 1 cm from the dentate line, without obstruction. The pathological diagnosis was adenocarcinoma. Enhanced CT revealed a tumor at the rectum below peritoneal reflection as well as swelling of the mesorectal lymph nodes. Multiple liver and lung metastases were also observed. The diagnosis was lower rectal cancer cT4aN2M1b(H2, PUL2), cStage Ⅳ. Chemotherapy was performed for disease control because of unresectable metastases. She received 7 courses of mFOLFOX plus bevacizumab. Further, as the metastatic lesion was inhibited, the primary lesion was excised for the purpose of symptom control. We judged that sphincter preservation was impossible because it was 1 cm away from the dentate line. She underwent robot-assisted abdominoperineal resection with D3 lymphadenectomy and sigmoid colostomy.

[A Case of Stage â £ Breast Cancer Treated with Mastectomy after Spontaneous Removal of a Cosmetic Breast Implant].

A 51-year-oldwoman came to our hospital complaining of a skin ulcer in the left breast. She hadpreviously undergone cosmetic breast augmentation by placement of a bag prosthesis under each mammary gland. She was diagnosed with Stage Ⅳ(T4bN1M1)breast cancer with multiple bone metastases. Following the diagnosis, 3 regimens of hormonal therapy were sequentially administered. The treatment was then switched to chemotherapy following confirmation of tumor progression in the left breast tumor. After 3 cycles of paclitaxel andbevacizumab as the second-line of chemotherapy, the size of the left breast tumor was remarkably reduced. Mastectomy with axillary lymph node sampling and removal of the implant were scheduled for local control. However, due to gradual exposure of the implant under the left breast, it was spontaneously removedfrom the original position when the patient was waiting for the surgery. Therefore, only mastectomy with axillary lymph node sampling was performed, followed by 45 Gy/25 times of postmastectomy and locoregional lymph node irradiation. Six months after the surgery, the patient is alive with no signs of local recurrence.

[A Resected Case of Hepatocellular Carcinoma Recurrence with Bile Duct Tumor Thrombus after RFA].

Hepatocellular carcinoma with bile duct invasion is rare, with a reported incidence of 3.4%. A 71-year-old man with hepatocellular carcinoma underwent radiofrequency ablation(RFA)(S6, S7, S8)and required readmission 22 months after the RFA for hepatocellular carcinoma recurrence detected by gadoxetic acid-enhanced magnetic resonance imaging. Enhanced abdominal computed tomography and magnetic resonance cholangiopancreatography revealed a tumor thrombus in a biliary branch and left adrenal gland metastases. We performed a right lobectomy and left adrenalectomy. The biliary thrombus was easily removed. Postoperative histopathological examination of the resected specimen showed a moderately differentiated hepatocellular carcinoma invading the biliary tract and the absence of viable cells in the liver tumor. The patient has shown no recurrence 6 months after the hepatectomy.

[Long-Term Survival in a Patient with Stage â £ Gastric Cancer Successfully Treated with Multidisplinary Treatment].

A man in his 60s who had epigastric pain was referred to our hospital and diagnosed with advanced type 3 gastric cancer with multiple liver metastases, cT4acN2cN1(H1), cStage Ⅳ(HER2 3+). He underwent chemotherapy using capecitabine, cisplatin(CDDP), and trastuzumab(T-mab)(XPT). After 7 courses of XPT and 23 courses of XT, liver metastases disappeared, and we decided to perform open distal gastrectomy, D2+ #18 lymphadenectomy, and Billroth Ⅰ reconstruction as a conversion surgery. Despite adjuvant chemotherapy with S-1 plus T-mab, multiple lymph nodes recurrence occurred 3 months after the surgery. He was found to be in complete remission as assessed by CT after 5 courses of second-line CPT-11 treatment, which was discontinued after 17 courses. The patient is alive without recurrence at 57 months after the initial treatment and 22 months after the last treatment.

[Sustained Complete Response of Hepatocellular Carcinoma with Multiple Intrahepatic Metastases following the Discontinuation of Sorafenib].

Sorafenib is an oral multi-targeted tyrosine kinase inhibitor used in cases of unresectable advanced HCC that significantly improves progression-free and overall survival. Complete response(CR)is uncommon; however, if major or complete radiological response are obtained, the issue of the discontinuation of sorafenib remains unresolved. The present study reported a case of a 75-year-old man with non-hepatitis B and C virus-related cirrhosis and multiple recurrent HCCs followingresection. In December 2010, a CT scan revealed multiple intrahepatic recurrence after TACE. Laboratory testingshowed Child-Pugh class A cirrhosis and an alpha-fetoprotein level of over 20,000 ng/mL. Sorafenib(800mg/day)was started in December 2010. The subsequent dynamic CT performed at the 6th month of therapy showed a partial response accordingto RECIST criteria and a complete response accordingto mRECIST. The AFP had decreased to within normal levels. In May 2012, the sorafenib dose was reduced(200 mgtwice daily)due to side effects(skin reaction). In December 2013, treatment was stopped after confirmation of a CR associated with shrinkage of the HCC. The patient maintained this remission until June 2018, more than 54 months after the discontinuation of sorafenib therapy. The adverse events of sorafenib were reversible. Further reportingof similar cases should help in the design of treatment strategies after CR to sorafenib therapy.

[A Resected Case of Tumorigenic Pancreatic Endocrine Cell Hyperplasia].

A 51-year-old man with a gallstone was found to have a tumor in the tail of the pancreas during preoperative examination. We performed EUS-FNA and a pancreatic neuroendocrine tumor was suspected.Therefore, laparoscopic distal pancreatectomy and cholecystectomy were performed.Pathological examination and immunohistochemistry showed that the pancreatic endocrine cells were uniformly increased and were composed of normal Langerhans islets.Therefore, the patient was diagnosed with pancreatic endocrine cell hyperplasia.Typical pancreatic endocrine cell hyperplasia does not form a tumor and is asymptomatic.However, some cases are symptomatic; therefore, when hypoglycemia or pancreatic hormone elevation are found without a clear cause, it should be distinguished.Because pancreatic tumors are difficult to diagnose definitely by imaging inspection alone, needle biopsy is necessary.However, neuroendocrine tumor and neuroendocrine cell hyperplasia are difficult to differentiate by biopsy.

[A Case of Strangulating Intestinal Obstruction Caused by Coiling of Low-Grade Appendiceal Mucinous Neoplasm to Terminal Ileum].

The patient was a 67-year-old female without a history of surgery. She presented with an abdominal pain and vomiting, and was rushed to our hospital. The abdominal pain was severe, but no peritoneal irritation sign was observed. Abdominal CT scan revealed a strangulating intestinal obstruction and accumulation of ascitic fluid. Emergency surgery was performed for diagnosis and treatment. The intraoperative finding showed serous ascitic fluid and strangulating intestinal obstruction caused by appendiceal tumor coiling around the terminal ileum, which had become ischemic with thinning of its wall. Ileocecal resection with removal of lymph nodes(D3)was performed. The postoperative course was uneventful, and the patient was discharged 13 days after the surgery. Pathological examination of the appendiceal tumor revealed a low-grade appendiceal mucinous neoplasm(LAMN)with no metastasis to the lymph nodes. We had a rare case of strangulating intestinal obstruction caused by coiling of LAMN to the terminal ileum.

[A Case of Leiomyosarcoma of the Sigmoidal Mesocolon].

Leiomyosarcoma of the mesocolon is a very rare disease. Previously, there was no recommendation for chemotherapy or radiotherapy for leiomyosarcoma of the mesocolon, and only surgical resection reportedly offers a chance for cure. However, the reported cases of leiomyosarcoma of the mesocolon were not distinguished from those of gastrointestinal stromal tumor (GIST), which is the same mesenchymal tumor; thus, there is a possibility that they include cases that should be diagnosed as GIST. We report a case of leiomyosarcoma of the sigmoidal mesocolon.

Capturing alternative secondary structures of RNA by decomposition of base-pairing probabilities.

BACKGROUND: It is known that functional RNAs often switch their functions by forming different secondary structures. Popular tools for RNA secondary structures prediction, however, predict the single 'best' structures, and do not produce alternative structures. There are bioinformatics tools to predict suboptimal structures, but it is difficult to detect which alternative secondary structures are essential. RESULTS: We proposed a new computational method to detect essential alternative secondary structures from RNA sequences by decomposing the base-pairing probability matrix. The decomposition is calculated by a newly implemented software tool, RintW, which efficiently computes the base-pairing probability distributions over the Hamming distance from arbitrary reference secondary structures. The proposed approach has been demonstrated on ROSE element RNA thermometer sequence and Lysine RNA ribo-switch, showing that the proposed approach captures conformational changes in secondary structures. CONCLUSIONS: We have shown that alternative secondary structures are captured by decomposing base-paring probabilities over Hamming distance. Source code is available from http://www.ncRNA.org/RintW .

Rtools: a web server for various secondary structural analyses on single RNA sequences.

The secondary structures, as well as the nucleotide sequences, are the important features of RNA molecules to characterize their functions. According to the thermodynamic model, however, the probability of any secondary structure is very small. As a consequence, any tool to predict the secondary structures of RNAs has limited accuracy. On the other hand, there are a few tools to compensate the imperfect predictions by calculating and visualizing the secondary structural information from RNA sequences. It is desirable to obtain the rich information from those tools through a friendly interface. We implemented a web server of the tools to predict secondary structures and to calculate various structural features based on the energy models of secondary structures. By just giving an RNA sequence to the web server, the user can get the different types of solutions of the secondary structures, the marginal probabilities such as base-paring probabilities, loop probabilities and accessibilities of the local bases, the energy changes by arbitrary base mutations as well as the measures for validations of the predicted secondary structures. The web server is available at http://rtools.cbrc.jp, which integrates software tools, CentroidFold, CentroidHomfold, IPKnot, CapR, Raccess, Rchange and RintD.

[Problems of Home-Visiting Speech-Language-Hearing Therapists in Dysphagia Management].

There are fewer reports by speech-language-hearing therapists than those by physical therapists or occupational therapists for visiting rehabilitation. Therefore, we examined the present situation with emphasis on professional roles of speech-language- hearing therapists working in visiting rehabilitation, patient tendency, and dysphagia rehabilitation. A questionnaire survey and interview survey were conducted on 6 speech-language-hearing therapists working in visiting rehabilitation. In the questionnaire, personal attributes, subject area, details of dysphagia rehabilitation, professional duties, and tendency of patient in charge were collected. In the interview survey, we asked about trends and request status, evaluation and training protocol for patients with dysphagia, activities related to pneumonia prevention, and future directions in the field. Results show that many linguistichearing experts worked with dysphagia patients, indicating that the needs for respiratory rehabilitation and dysphagia rehabilitation are high. In this survey, the environment surrounding visiting speech-language-hearing therapists and patients with dysphagia was clarified.

[A Case of Rectal Cancer with Multiple Endocrine Neoplasia Type 2].

A 63-year-old man with multiple endocrine neoplasia type 2(MEN2)was admitted to the hospital because of positive fecal occult blood tests. Colonoscopy revealed a 50mm type 2 tumor at the rectum, which was diagnosed as an adenocarcinoma based on histology. Since there was no apparent distant metastasis, laparoscopy-assisted low anterior resection with regional lymph node dissection was performed. The final diagnosis was pT3, pN0, pM0, pStage II . Almost all patients with MEN2 have RET mutations, and they are resistant to EGFR inhibitors. Those who have thyroid cancer with RET mutations are often given a RET kinase inhibitor. In this case, if the patient develops recurrent rectal cancer, it warrants checking for RET mutations and using a multi-kinase inhibitor.

[A Case of Gastric Schwannoma with Regional Lymphadenopathy].

Schwannomas are rarely observed in the gastrointestinal tract. A 63-year-old man was referred to our hospital with gastric submucosal tumor with central ulceration by upper gastrointestinal endoscopy. Biopsy was performed, but pathological diagnosis was not obtained. A contrast-enhanced computed tomography scan of the abdomen revealed a round mass in the lower part of the stomach and regional lymphadenopathies. A distal gastrectomy with dissection of the regional lymph nodes (D2)was performed. The submucosal tumor measuring 67×49mm was resected. Histopathological examination revealed spindle-shaped cells arranged in palisades. The specimen was positive for S-100 protein, but negative for desmin, SMA, c-kit, and CD34. No tumor cells were found in the resected enlarged lymph nodes, indicating reactive lymphadenopathies. Based on these findings, the tumor was identified as a benign gastric schwannoma. Our patient shows no recurrence at 6 month follow-up.

[Treatment Outcomes of Gemcitabine and Cisplatin Combination Therapy for Unresectable and Recurrent Biliary Tract Cancer].

Gemcitabine and cisplatin combination therapy(GC therapy)is now considered a highly effective regimen for patients with unresectable and metastatic biliary tract cancer. We performed GC therapy for 18 patients between January 2014 and April 2018. The median age of the patients was 67.5 years, and 13 patients were men. Fifteen patients had a performance status (PS)score of 0, and 3 patients had a PS score of 1. Nine patients had distal cholangiocarcinoma, 3 had intrahepatic cholangiocarcinoma, 3 had duodenum papilla cancer, and 3 had gallbladder cancer. Fourteen patients showed recurrence after the radical resection, and 9 had liver metastasis. Sixteen patients had over Grade 3 hematological or non-hematological toxicities. The most-common adverse event was neutropenia. None of the patients had Grade 5 adverse events. The response rate was 11.1%, and the disease-control ratio was 66.7%. GC therapy was effective for patients with unresectable and recurrent biliary tract cancer. However, it is necessary to examine the eligibility of patients before treatment.