The lipid mediator protectin D1 inhibits influenza virus replication and improves severe influenza.

Influenza A viruses are a major cause of mortality. Given the potential for future lethal pandemics, effective drugs are needed for the treatment of severe influenza such as that caused by H5N1 viruses. Using mediator lipidomics and bioactive lipid screen, we report that the omega-3 polyunsaturated fatty acid (PUFA)-derived lipid mediator protectin D1 (PD1) markedly attenuated influenza virus replication via RNA export machinery. Production of PD1 was suppressed during severe influenza and PD1 levels inversely correlated with the pathogenicity of H5N1 viruses. Suppression of PD1 was genetically mapped to 12/15-lipoxygenase activity. Importantly, PD1 treatment improved the survival and pathology of severe influenza in mice, even under conditions where known antiviral drugs fail to protect from death. These results identify the endogenous lipid mediator PD1 as an innate suppressor of influenza virus replication that protects against lethal influenza virus infection.

Wastewater-based reproduction numbers and projections of COVID-19 cases in three areas in Japan, November 2021 to December 2022.

BackgroundWastewater surveillance has expanded globally as a means to monitor spread of infectious diseases. An inherent challenge is substantial noise and bias in wastewater data because of the sampling and quantification process, limiting the applicability of wastewater surveillance as a monitoring tool.AimTo present an analytical framework for capturing the growth trend of circulating infections from wastewater data and conducting scenario analyses to guide policy decisions.MethodsWe developed a mathematical model for translating the observed SARS-CoV-2 viral load in wastewater into effective reproduction numbers. We used an extended Kalman filter to infer underlying transmissions by smoothing out observational noise. We also illustrated the impact of different countermeasures such as expanded vaccinations and non-pharmaceutical interventions on the projected number of cases using three study areas in Japan during 2021-22 as an example.ResultsObserved notified cases were matched with the range of cases estimated by our approach with wastewater data only, across different study areas and virus quantification methods, especially when the disease prevalence was high. Estimated reproduction numbers derived from wastewater data were consistent with notification-based reproduction numbers. Our projections showed that a 10-20% increase in vaccination coverage or a 10% reduction in contact rate may suffice to initiate a declining trend in study areas.ConclusionOur study demonstrates how wastewater data can be used to track reproduction numbers and perform scenario modelling to inform policy decisions. The proposed framework complements conventional clinical surveillance, especially when reliable and timely epidemiological data are not available.

Mitochondrial glutathione peroxidase 4 is indispensable for photoreceptor development and survival in mice.

Glutathione peroxidase 4 (GPx4) is known for its unique function in the direct detoxification of lipid peroxides in the cell membrane and as a key regulator of ferroptosis, a form of lipid peroxidation-induced nonapoptotic cell death. However, the cytosolic isoform of GPx4 is considered to play a major role in inhibiting ferroptosis in somatic cells, whereas the roles of the mitochondrial isoform of GPx4 (mGPx4) in cell survival are not yet clear. In the present study, we found that mGPx4 KO mice exhibit a cone-rod dystrophy-like phenotype in which loss of cone photoreceptors precedes loss of rod photoreceptors. Specifically, in mGPx4 KO mice, cone photoreceptors disappeared prior to their maturation, whereas rod photoreceptors persisted through maturation but gradually degenerated afterward. Mechanistically, we demonstrated that vitamin E supplementation significantly ameliorated photoreceptor loss in these mice. Furthermore, LC-MS showed a significant increase in peroxidized phosphatidylethanolamine esterified with docosahexaenoic acid in the retina of mGPx4 KO mice. We also observed shrunken and uniformly condensed nuclei as well as caspase-3 activation in mGPx4 KO photoreceptors, suggesting that apoptosis was prevalent. Taken together, our findings indicate that mGPx4 is essential for the maturation of cone photoreceptors but not for the maturation of rod photoreceptors, although it is still critical for the survival of rod photoreceptors after maturation. In conclusion, we reveal novel functions of mGPx4 in supporting development and survival of photoreceptors in vivo.

Economic Evaluation of Wastewater Surveillance Combined with Clinical COVID-19 Screening Tests, Japan.

The COVID-19 pandemic has imposed substantial burdens on the global society. To find an optimal combination of wastewater surveillance and clinical testing for tracking COVID-19, we evaluated the economic efficiency of hypothetical screening options at a single facility in Japan. To conduct cost-benefit analyses, we developed standard decision models in which we assumed model parameters from literature and primary data, such as screening policies used at the Tokyo Olympic and Paralympic Village in 2021. We compared hypothetical 2-step screening options that used clinical PCR to diagnose COVID-19 after a positive result from primary screening using antigen tests (option 1) or wastewater surveillance (option 2). Our simulation results indicated that option 2 likely would be economically more justifiable than option 1, particularly at lower incidence levels. Our findings could help justify and promote the use of wastewater surveillance as a primary screening at a facility level for COVID-19 and other infectious diseases.

[A Case of Giant Abdominal Desmoid Tumor in a Young Man].

Desmoid tumor is a rare tumor of the soft tissue. The frequency of occurrence is 2.4 to 4.3 cases per year per million people, which is a very rare disease. We experienced a huge intra-abdominal desmoid tumor which is thought to be the primary mesentery. The case was a male in his 20s. He visited a nearby doctor with a complaint of abdominal bloating and abdominal pain. Abdominal contrast CT revealed a huge abdominal mass with a clear boundary of 35×25 cm in size extending from the upper right abdomen to the pelvis. Surgery was performed with a diagnosis of an intra-abdominal mass. Open abdominal tumor resection. Due to infiltration into the duodenum, transverse colon, and pancreas, right hemicolectomy and duodenal combined resection were performed. The pathological diagnosis was a diagnosis of desmoid tumor.

[A Case of Liver Metastasis of Gastric Cancer Successfully Treated with SOX plus Nivolumab].

An 82-year-old, male. He visited his local doctor with a chief complaint of dyspnea on exertion. Anemia was noted, and upper gastrointestinal endoscopy was performed, which revealed an ulcerative lesion in the gastric antrum. A biopsy revealed Group 5, tub2, and HER2 negative, with PD-L1≥5%. cT3N1H1(M1 HEP), cStage ⅣB was diagnosed based on CT scan showing enlarged #8 lymph node and a single liver metastasis in the 2 cm range in S6 of the liver. The patient was deemed unresectable and was started on SOX plus nivolumab therapy. On day 11 after initiation, the patient had Grade 3 diarrhea by CTCAE v5.0, and S-1 was withdrawn for 3 days, but was administered for 2 courses. CT and MRI after chemotherapy showed shrinkage of both the primary tumor and liver metastases; R0 resection was deemed possible, and pyloric gastrectomy, D2 lymph node dissection, and partial hepatic S6 resection were performed. The histological evaluation of response to treatment was Grade 1b, and the patient was in ypStage ⅠA. The patient has been alive without recurrence for 6 months postoperatively while receiving S-1 monotherapy on an outpatient basis.

[A Case of Gastric Cancer Performed Curative Operation after Nivolumab].

A 69-year-old man was admitted for the severe anemia. Upper gastrointestinal endoscopy revealed type 3 gastric cancer (por1, HER2 negative)that spread from EG junction to the lesser curvature of lower gastric body. CT revealed LNs metastasis and the direct invasion to the diaphragm. We diagnosed the locally advanced gastric cancer(T4bN[+]M0, Stage ⅣA) and planed neoadjuvant chemotherapy. After 3 courses of S-1 plus CDDP therapy, serum CEA level increased. And the invasion to diaphragm was unclear although the tumor shrunk. After 3 courses of nab-PTX plus RAM therapy as the second- line, the tumor was PD. As the third-line chemotherapy, nivolumab therapy was repeated up to a total of 15 courses. As the tumor was PR, the patient underwent total gastrectomy with D2 lymphadenectomy. The histopathological examination revealed that the cancer invaded into the muscle layer without lymph nodes metastasis. The cancer was diagnosed as pT2 (MP)N0M0, Stage ⅠB. The cancer cells were EB virus positive and MSI-high. CD 8 positive T lymphocytes infiltrated into the stroma. The patient is alive 26 months without adjuvant chemotherapy. The curative operation was able to perform because the infiltrative CD8 positive T lymphocytes reactivated with nivolumab responded remarkably.

[A Case of Primary Hepatic Mucosa-Associated Lymphoid Tissue Lymphoma].

A 74-year-old man with no chronic liver disease was admitted for an incidental liver tumor by computed tomography. Serological examinations for hepatitis B and C virus were negative and tumor markers, including carcinoembryonic antigen, α-fetoprotein, carbohydrate antigen 19-9, and des-gamma-carboxy prothrombin, were within the normal range. The contrast- enhanced magnetic resonance imaging revealed that the 26 mm in diameter patchy tumor occupied the S7 in the liver. The tumor boundary was enhanced slightly in the arterial phase and inside gradually in the portal phase, and the enhancement was faded in the late phase. As a characteristic finding, vessels penetrated the tumor. The tumor was diagnosed as cholangiocarcinoma, and the patient underwent right lateral sectionectomy. After 19 days postoperatively, the patient was discharged. The diagnosis of hepatic mucosa-associated lymphoid tissue(MALT)lymphoma was made by pathological examination. Currently, the patient has no recurrence for 5 months without adjuvant chemotherapy. The primary hepatic MALT lymphoma is a rare disease among primary hepatic malignant lymphomas. The patient must be followed up carefully because 2 cases were reported as recurrent cases after several years postoperatively although the disease has a good prognosis.

[A Case of Laparoscopically Resected Sigmoid Colon Cancer and Transverse Colon Mesentery Primary Solitary Fibrous Tumor].

The patient is a 52-year-old woman who visited the general practitioner because of positive fecal occult blood test by medical examination. The patient underwent colonoscopy at the hospital, which revealed sigmoid colon cancer. Therefore, the patient was referred to our hospital for surgery. Preoperative CT scan revealed a well-defined and lobulated 54 mm tumor on the caudal side of the duodenal third portion. On MRI, the tumor showed low T1-weighted image signal and high T2-weighted and diffusion-weighted images signal, with low ADC. For preoperative diagnosis, we diagnosed sigmoid colon cancer and transverse colon mesenteric and performed laparoscopic sigmoid colon and transverse colon mesenteric tumor resections. The histopathological tumor diagnoses were sigmoid colon cancer(S, type 2, 30×30 mm, 1/2 circumference, moderately differentiated adenocarcinoma, pT3[SS], INF b, Ly1a, V1a, pN1b[#252: 2/4], sM0, fStage Ⅲb)and transverse colon mesentery primary solitary fibrous tumor. The patient was treated with XELOX as the adjuvant chemotherapy and survived without recurrence until present.

[Long-Term Survival following Multidisciplinary Therapy for Unresectable Pancreatic Body Cancer].

A 57-year-old man was diagnosed with a tumor in the pancreatic body at a nearby hospital and consulted our hospital. Examinations revealed that carbohydrate antigen 19-9(CA19-9)levels were 1,765.0 U/mL. We confirmed metastatic liver tumors in S4 and S8 of the liver by EOB-MRI. We diagnosed unresectable pancreatic cancer(T3N0M1, cStage Ⅳ)and administered 10 courses of gemcitabine(GEM)plus nab-paclitaxel(nab-PTX)therapy. The main lesion and the lesion in S4 subsequently disappeared, and the lesion in S8 degenerated into a cyst. CA19-9 levels were 113 U/mL. Surgery was determined as the best course of action after normalizing CA19-9 levels. Therefore, we further administered 6 courses of FOLFIRINOX therapy and 4 courses of GEM plus nab-PTX therapy, but CA19-9 was not normalized. We decided that it would be difficult to normalize CA19-9, and thus proceeded with surgery. During the operation, cystic degenerative lesions were found in S8 and peritoneal dissemination was found in the transverse mesentery. Because the ascites cytopathology was negative, it was judged that the peritoneal dissemination was localized. We performed distal pancreatectomy(D2)plus partial hepatectomy(S8)plus peritoneal dissemination resection. On day 52 after surgery, we resumed GEM plus nab-PTX. The patient has survived without any recurrence for 3 years after the initial surgery.

[A Case of Giant Pancreatic Mucinous Cystic Neoplasm That Was Difficult to Preoperative Diagnosis].

A 43-year-old woman with about abdominal distension was referred to our hospital for a more detailed examination. Abdominal CT showed 27 cm-sized cystic lesion with the calcification along the partition wall and a nodular hyperplasia. We suspected pancreatic pseudocyst, primary retroperitoneal tumor and we performed tumorectomy. The resected specimen had a maximum diameter of 27 cm. The histopathological diagnosis was mucinous cystadenocarcinoma of the pancreas with ovarian-type stroma. The adjuvant chemotherapy treated with gemcitabine was selected for 3 courses. She continues to do well without any recurrences 7 months later.

[A Case of Pancreas Neuroendocrine Carcinoma Achieved Long-Term Survival by Carboplatin plus Etoposide Therapy].

A 70-year-old man with the history of diabetes mellitus complained of lower abdominal discomfort. Abdominal ultrasonography revealed a pancreatic mass. Contrast enhanced CT showed a 2.6 cm-enhanced tumor ventral to the pancreatic head. It was diagnosed with a pancreatic neuroendocrine carcinoma(PanNEC-G3)by EUS-FNA. The patient underwent pancreatoduodenectomy with the wedge resection of the portal vein and partial resection of the transverse colon. We administered 6 cycles of adjuvant therapy with CDDP plus CPT-11. With the presentation of lymph node metastases and the local recurrence in the anastomotic site of the transverse colon 15 months after surgery, the patient received carboplatin plus etoposide(CE)therapy. Although local recurrence completely responded to the CE therapy, bone metastases were detected 27 months after surgery. Metastatic lesion did not respond to systemic chemotherapy including gemcitabine plus nab-paclitaxel and nal-IRI plus 5-FU/LV, and the patient eventually died 37 months after the surgery. PanNECs represent for less than 1% of all pancreatic tumor. They are characterized by high malignant potential and short time survival with the reported OS of 8.5 to 21 months. This case served as an important reminder to consider multimodal treatment for PanNEC patients to obtain longer survival.

Autophagosome-lysosome fusion in neurons requires INPP5E, a protein associated with Joubert syndrome.

Autophagy is a multistep membrane traffic pathway. In contrast to autophagosome formation, the mechanisms underlying autophagosome-lysosome fusion remain largely unknown. Here, we describe a novel autophagy regulator, inositol polyphosphate-5-phosphatase E (INPP5E), involved in autophagosome-lysosome fusion process. In neuronal cells, INPP5E knockdown strongly inhibited autophagy by impairing the fusion step. A fraction of INPP5E is localized to lysosomes, and its membrane anchoring and enzymatic activity are necessary for autophagy. INPP5E decreases lysosomal phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), one of the substrates of the phosphatase, that counteracts cortactin-mediated actin filament stabilization on lysosomes. Lysosomes require actin filaments on their surface for fusing with autophagosomes. INPP5E is one of the genes responsible for Joubert syndrome, a rare brain abnormality, and mutations found in patients with this disease caused defects in autophagy. Taken together, our data reveal a novel role of phosphoinositide on lysosomes and an association between autophagy and neuronal disease.

[A Case of Long-Term Survival with Far Advanced Gastric Cancer after Multidisciplinary Treatments, including Conversion Surgery].

An 82-year-old man with Stage Ⅳ advanced gastric cancer and multiple liver metastases was referred to our hospital. Chemotherapy using S-1 was administered, resulting in withdrawal from the usual course because of an adverse event of grade 4 anorexia. GIS and EOB-MRI showed a prominent tumor reduction in both lesions; however, despite this, distal gastrectomy, D2 lymph node dissection, liver biopsy for S3 lesion, partial liver resection for S6 lesion, and cholecystectomy were performed to obtain a therapeutic diagnosis. Pathology revealed that the tumor cells remained in the main liver metastatic lesions. Therapeutic effect was assessed as Grade 2. Although weekly paclitaxel followed by reduced S-1 dosage was introduced after surgery, the recurrent mass was observed in the para-aortic region after 2 years. Subsequently, para-aortic lymph node dissection was performed because no new lesion was detected. More than 10 years have passed without any recurrence since the first surgery. As part of a multidisciplinary treatment for far advanced gastric cancer with multiple liver metastases (Stage Ⅳ), conversion surgery might be considered effective.

[A Case of Esophageal Neuroendocrine Carcinoma(NEC)Treated with Collective Treatment].

A 68-year-old man presented to our hospital. An upper gastrointestinal tract endoscopy performed elsewhere revealed an elevated lesion with a circumferential esophageal cancer(identified as small cell carcinoma). Perthe treatment forsmall cell cancer and the standard treatment for esophageal neuroendocrine carcinoma, 7 courses of CBDCA(5mg/m2)plus ETP (100mg/m2)were administered. The lesion shrank and the lymph node swelling disappeared and the patient was deemed to be in partial remission. Nine months later, however, the primary tumor increased in size. A transthoracic subtotal esophagectomy( laparoscope-assisted), 2 area dissection, and gastric tube reconstruction(post-sternal)were performed at 2 years and 10 months afterdiagnosis.

ErbB1 and ErbB4 generate opposing signals regulating mesenchymal cell proliferation during valvulogenesis.

Heparin-binding EGF-like growth factor (HB-EGF) plays an indispensable role in suppression of cell proliferation during mouse valvulogenesis. However, ligands of the EGF receptor (EGFR/ErbB1), including HB-EGF, are generally considered as growth-promoting factors, as shown in cancers. HB-EGF binds to and activates ErbB1 and ErbB4. We investigated the role of ErbB receptors in valvulogenesis in vivo using ErbB1- and ErbB4-deficient mice, and an ex vivo model of endocardial cushion explants. We show that HB-EGF suppresses valve mesenchymal cell proliferation through a heterodimer of ErbB1 and ErbB4, and an ErbB1 ligand (or ligands) promotes cell proliferation through a homodimer of ErbB1. Moreover, a rescue experiment with cleavable or uncleavable isoforms of ErbB4 in ERBB4-null cells indicates that the cleavable JM-A, but not the uncleavable JM-B, splice variant of ErbB4 rescues the defect of the null cells. These data suggest that the cytoplasmic intracellular domain of ErbB4, rather than the membrane-anchored tyrosine kinase, achieves this suppression. Our study demonstrates that opposing signals generated by different ErbB dimer combinations function in the same cardiac cushion mesenchymal cells for proper cardiac valve formation.

Endothelial cells are intrinsically defective in xenophagy of Streptococcus pyogenes.

Group A Streptococcus (GAS) is deleterious pathogenic bacteria whose interaction with blood vessels leads to life-threatening bacteremia. Although xenophagy, a special form of autophagy, eliminates invading GAS in epithelial cells, we found that GAS could survive and multiply in endothelial cells. Endothelial cells were competent in starvation-induced autophagy, but failed to form double-membrane structures surrounding GAS, an essential step in xenophagy. This deficiency stemmed from reduced recruitment of ubiquitin and several core autophagy proteins in endothelial cells, as demonstrated by the fact that it could be rescued by exogenous coating of GAS with ubiquitin. The defect was associated with reduced NO-mediated ubiquitin signaling. Therefore, we propose that the lack of efficient clearance of GAS in endothelial cells is caused by their intrinsic inability to target GAS with ubiquitin to promote autophagosome biogenesis for xenophagy.

[A Resected Case of Rectal Metastasis from Gastric Cancer].

An 82-year-oldwoman previously underwent total gastrectomy for gastric cancer at the age of 75 years. After 7 years of follow-up, a colonoscopy was performedto investigate the cause of constipation, which revealedan irregularity in the rectal submucosa. A colonoscopy-guidedbiopsy showedpoorly differentiatedad enocarcinoma, andthe immunohistochemical staining pattern showedMUC2(-), MUC5AC(+), CDX2(+), andCA1 25(-). FDG-PET showedintense uptake only at the rectum. Thus, laparoscopic high anterior resection was performed. Pathological findings showed that poorly differentiated adenocarcinoma and signet-ring cell carcinoma hadd evelopedmainly in the submucosa. In comparison with the immunohistological features of the previous gastric cancer, the rectal tumor hadsimilar morphological characteristics. The definitive diagnosis was rectal metastasis from gastric cancer. She has remained recurrence-free in the 20 months since this operation.

[HER2-Positive Advanced Gastric Cancer with Para-Aortic Lymph Node Metastases Treated with Conversion Surgery after Chemotherapy-A Case Report].

A 56-year-old woman diagnosed with type 2 gastric cancer and multiple lymph node metastases(T3N3M1[lym], cStage Ⅳ)was treated with chemotherapy using trastuzumab with S-1 plus cisplatin for 6 cycles. The primary lesion showed PR, and lymph node metastases disappeared after the chemotherapy. Because of adverse events, she was administered with 2 additional cycles of trastuzumab with S-1 plus cisplatin and 6 cycles of trastuzumab with capecitabine plus oxaliplatin. However, the primary lesion increased in size. Therefore, she underwent distal gastrectomy and D1+ lymphadenectomy with para-aortic lymph node sampling as a conversion surgery. The pathological diagnosis was T2N0M0, pStage ⅠB, and the primary cancer was Grade 1a owing to the chemotherapeutic effect. She survives without recurrence or postoperative adjuvant therapies 3 years after the surgery.

[A Case of Far-Advanced Esophageal Cancer with Multiple Metastases Showing Long-Term Survival after Chemotherapy].

A 71-year-oldman with voice hoarseness was referredto our hospital for further examination. He was diagnosedwith unresectable Stage Ⅳb esophageal cancer, with direct invasion to the aorta andtrachea andmultiple metastases to the lymph nodes, lungs, and adrenal gland. Because his performance status(PS)was deemedto be favorable, he receivedchemotherapy with docetaxel(DOC), cisplatin, and5 -FU(DCF therapy). After 2 cycles of DCF therapy, the primary lesion was scarred. No malignant lesions were detected in the biopsy performed. No distant metastases were identified on PET-CT. As a subsequent treatment, S-1 plus DOC therapy was administered. Finally, single S-1 administration was continued. The treatment periodwas 14 months. Treatment was concludedbecause a complete response(CR)was maintained. Three years after the conclusion of treatment, CR remains maintained. The overall survival in cases of unresectable advanced esophageal cancer is saidto be 3-10 months, but there are remarkable cases such as this one. If a goodPS is maintained, treatment shouldbe actively considered because CR is possible.