A SARS-CoV-2-specific CAR-T-cell model identifies felodipine, fasudil, imatinib, and caspofungin as potential treatments for lethal COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-induced cytokine storm is closely associated with coronavirus disease 2019 (COVID-19) severity and lethality. However, drugs that are effective against inflammation to treat lethal COVID-19 are still urgently needed. Here, we constructed a SARS-CoV-2 spike protein-specific CAR, and human T cells infected with this CAR (SARS-CoV-2-S CAR-T) and stimulated with spike protein mimicked the T-cell responses seen in COVID-19 patients, causing cytokine storm and displaying a distinct memory, exhausted, and regulatory T-cell phenotype. THP1 remarkably augmented cytokine release in SARS-CoV-2-S CAR-T cells when they were in coculture. Based on this "two-cell" (CAR-T and THP1 cells) model, we screened an FDA-approved drug library and found that felodipine, fasudil, imatinib, and caspofungin were effective in suppressing the release of cytokines, which was likely due to their ability to suppress the NF-κB pathway in vitro. Felodipine, fasudil, imatinib, and caspofungin were further demonstrated, although to different extents, to attenuate lethal inflammation, ameliorate severe pneumonia, and prevent mortality in a SARS-CoV-2-infected Syrian hamster model, which were also linked to their suppressive role in inflammation. In summary, we established a SARS-CoV-2-specific CAR-T-cell model that can be utilized as a tool for anti-inflammatory drug screening in a fast and high-throughput manner. The drugs identified herein have great potential for early treatment to prevent COVID-19 patients from cytokine storm-induced lethality in the clinic because they are safe, inexpensive, and easily accessible for immediate use in most countries.

Latest developments in chronic intestinal pseudo-obstruction.

Chronic intestinal pseudo-obstruction (CIPO) is a type of intestinal dysfunction presenting as symptoms of intestinal obstruction but without actual mechanical obstruction. An extremely low incidence, non-specific clinical symptoms, strong heterogeneity, and no definitive cause in some patients make CIPO very difficult to diagnose correctly. Imaging and gastrointestinal manometry are commonly used. Most patients have progressive worsening of their symptoms and require intervention, and nutritional assessment and treatment are very important to determine the prognosis. With improvements in surgical techniques, small bowel transplantation is a feasible treatment option for patients with advanced CIPO; however, the long-term prognosis for CIPO patients remains unsatisfactory. Generally, the disease is rare and difficult to diagnose, which leads to clinicians' lack of understanding of the disease and results in a high rate of misdiagnosis. This review describes the characteristics of CIPO and the latest developments in diagnosis and treatment, in detail. The goal of our review is to improve clinicians' understanding of CIPO so that the disease is identified quickly and accurately, and treated as early as possible to improve patients' quality of life.

Interleukin-1 receptor antagonist enhances chemosensitivity to fluorouracil in treatment of Kras mutant colon cancer.

BACKGROUND: Kras mutant colon cancer shows abnormal activation of the nuclear factor kappa-B (NF-κB) pathway, resulting in the proliferation of tumor cells. Treatment with fluorouracil (5-FU) might not achieve the expected inhibition of proliferation of malignant cells based on the fluorouracil-induced activation of the NF-κB pathway. AIM: To detect whether interleukin (IL)-1 receptor antagonist (IL-1RA) could increase the chemosensitivity to 5-FU by decreasing the activation of the NF-κB pathway and reducing the proliferation of colon cancer cells. METHODS: Western blot analysis was performed to detect the persistent activation of the NF-κB pathway in colon cancer cell lines. Reverse transcription-polymerase chain reaction was used to detect the IL-1RA-reduced expression levels of IL-6, IL-8, IL-17, IL-21 and TLR4 in colon cancer cell lines. We used a xenograft nude mouse model to demonstrate the downregulation of the NF-κB pathway by blocking the NF-κB-regulated IL-1α feedforward loop, which could increase the efficacy of chemotherapeutic agents in inhibiting tumor cell growth. RESULTS: IL-1 receptor antagonist could decrease the expression of IL-1α and IL-1ß and downregulate the activity of the NF-κB pathway in Kras mutant colon cancer cells. Treatment with 5-FU combined with IL-1RA could increase the chemosensitivity of the SW620 cell line, and decreased expression of the TAK1/NF-κB and MEK pathways resulted in limited proliferation in the SW620 cell line. CONCLUSION: Adjuvant chemotherapy with IL-1RA and 5-FU has a stronger effect than single chemotherapeutic drugs. IL-1RA combined with fluorouracil could be a potential neoadjuvant chemotherapy in the clinic.

A rare case of acute primary omental infarction.

Primary omental infarction (POI) is a rare cause of acute abdomen. Most patients have aggravating abdominal pain without gastrointestinal symptoms. Here, we report a case of omental infarction in a 50-year-old woman, who had left abdominal pain and intestinal obstruction. Preoperative computed tomography (CT) of the abdomen showed a left ovarian cyst measuring 6.0 cm × 4.5 cm but otherwise seemed normal initially. The white blood cell count was 9.71 × 109/L, and D-dimer was 1.58 mg/L. Laparoscopic exploration was performed 1 day after admission because of peritonitis and intestinal obstruction. During the exploration, a segment of congested necrotic omentum was found adhering to the abdominal wall with a segment of small intestine. Bloody ascites was also observed in the abdominal cavity. We resected the nonviable segmental omentum, and the ovarian cyst was removed by the gynecologist using laparoscopic procedures. Final pathological findings confirmed POI. While reanalyzing the preoperative CT, a segmental fat mass with an increased density was noted in the left lower quadrant, which was consistent with the intraoperative view 6 days after surgery. The patient recovered uneventfully and was discharged.

OsCLT1, a CRT-like transporter 1, is required for glutathione homeostasis and arsenic tolerance in rice.

Arsenic (As) contamination in a paddy environment can cause phytotoxicity and elevated As accumulation in rice (Oryza sativa). The mechanism of As detoxification in rice is still poorly understood. We isolated an arsenate (As(V))-sensitive mutant of rice. Genomic resequencing and complementation identified OsCLT1, encoding a CRT-like transporter, as the causal gene for the mutant phenotype. OsCLT1 is localized to the envelope membrane of plastids. The glutathione and γ-glutamylcysteine contents in roots of Osclt1 and RNA interference lines were decreased markedly compared with the wild-type (WT). The concentrations of phytochelatin PC2 in Osclt1 roots were only 32% and 12% of that in WT after As(V) and As(III) treatments, respectively. OsCLT1 mutation resulted in lower As accumulation in roots but higher As accumulation in shoots when exposed to As(V). Under As(III) treatment, Osclt1 accumulated a lower As concentration in roots but similar As concentration in shoots to WT. Further analysis showed that the reduction of As(V) to As(III) was decreased in Osclt1. Osclt1 was also hypersensitive to cadmium (Cd). These results indicate that OsCLT1 plays an important role in glutathione homeostasis, probably by mediating the export of γ-glutamylcysteine and glutathione from plastids to the cytoplasm, which in turn affects As and Cd detoxification in rice.

Digestive tract hemorrhage due to complications with gastrointestinal stromal tumor treated with sunitinib: A case report.

Gastrointestinal stromal tumors (GISTs) are rare, and account for 1% of all gastrointestinal neoplasms. GISTs are the most frequent mesenchymal tumors of the gastrointestinal tract. However, the clinical and pathological characteristics of these neoplasms are not adequately understood. The best treatment approach for GISTs remains unclear. In the present study, we report a case of a GIST originating from the stomach. A digestive tract hemorrhage occurred as a complication of sunitinib treatment. This is the first report of a digestive tract hemorrhage due to sunitinib treatment.

The active alkaloids of Gelsemium elegans Benth. are potent anxiolytics.

RATIONALE: An increasing number of herbal products has been introduced to treat anxiety and depression. Gelsemium elegans Benth (G. elegans) is a well-known herbal plant in Asia. Four major alkaloids (gelsemine, koumine, gelsevirine, and gelsenicine) have been isolated from G. elegans. Recently, interest has arisen to investigate the pharmaceutical potential of G. elegans alkaloids in the context of neuropsychopharmacology. OBJECTIVES: We investigated whether G. elegans alkaloids are capable of producing anxiolytic and antidepressant effects in mouse models. In particular, we examined whether the anxiolytic action of G. elegans alkaloids is due to the agonist effects of glycine receptor in the brain. METHODS: Two mouse models (elevated plus-maze and light-dark transition model) were used to examine potential anxiolytic effects. Forced swim test and tail suspension test were used to test the antidepressive action of G. elegans alkaloids. Moreover, we also explored the anxiolytic mechanisms of G. elegans alkaloids by intracerebroventricular administration of strychnine, an antagonist of glycine receptor, in the elevated plus-maze. RESULTS: Gelsemine, koumine, and gelsevirine, but not gelsenicine, exhibited potent anxiolytic effects in the two anxiety models. None of the four G. elegans alkaloids exerted antidepressant effects in the two depression models. None of G. elegans alkaloids impaired spontaneous motor activities. The intracerebroventricular administration of strychnine significantly antagonized the anxiolytic effects of gelsemine, koumine, and gelsevirine administrated subcutaneously. CONCLUSIONS: Gelsemine, koumine, and gelsevirine could be developed as the treatment of anxiety-related disorders in human patients. Their anxiolytic mechanism may be involved in the agonist action of glycine receptor in the brain.

Anti-HIV activities of the compounds isolated from Polygonum cuspidatum and Polygonum multiflorum.

The 70 % EtOH extract of Polygonum cuspidatum showed inhibitory action against HIV-1-induced syncytium formation at non-cytotoxic concentrations in vitro with a 50 % effective concentration (EC(50)) of 13.94 +/- 3.41 microg/mL. Through bioactivity-guided fractionation, 20 phenolic compounds, including eight stilbenoids, were isolated from the roots of Polygonum cuspidatum, and their anti-HIV-1 activities were evaluated. Results showed that compounds 1, 13, 14, and 16 demonstrated fairly strong antiviral activity against HIV-1-induced cytopathic effects in C8166 lymphocytes at non-cytotoxic concentrations, with EC (50) values of 4.37 +/- 1.96 microg/mL, 19.97 +/- 5.09, 14.4 +/- 1.34 microg/mL, and 11.29 +/- 6.26 microg/mL and therapeutic index (TI) values of 8.12, > 10.02, > 13.89, and > 17.71, respectively. Other compounds showed either weak or no effects. Compound 6 also showed weak inhibition (153.42 +/- 19.25 microg/mL); however, it possesses very good water solubility and showed almost no cytotoxicity (> 2000 microg/mL), therefore achieving a fairly good TI (13.04). The activities of the two compounds (3 and 18) from Polygonum multiflorum were also assayed. The relationship between molecular structures and their bioactivities was also discussed.

Di-µ-thio-cyanato-κN:N-bis-({2,4-di-bromo-6-[2-(methyl-amino)ethyl-imino-meth-yl]-phenol-ato-κN,N',O}nickel(II)).

The title complex, [Ni(2)(C(11)H(11)Br(2)N(2)O)(2)(NCS)(2)], is a thio-cyanate-bridged dinuclear nickel(II) complex. The asymmetric unit contains two molecules. Both Ni atoms in each molecule have a square-pyramidal coordination geometry, and each center is bound by one O and two N atoms of one Schiff base ligand and by one N atom of a bridging thio-cyanate ligand, which define the basal planes. N atoms from the bridging thio-cyanate ligands occupy the apical positions.

(E)-N'-(5-Bromo-2-methoxy-benzyl-idene)-4-chloro-benzohydrazide.

The title Schiff base compound, C(15)H(12)BrClN(2)O(2), crystallizes with two independent mol-ecules in the asymmetric unit. The mol-ecules adopt an E configuration with respect to the C=N double bond. The dihedral angles between the benzene rings are 24.4 (2) and 9.4 (2)° in the two mol-ecules. The crystal structure is stabilized by inter-molecular N-H⋯O hydrogen bonds, forming chains running along the b axis.

[Diagnosis and management of metastatic pancreatic tumors].

OBJECTIVE: To study the clinicopathological features and prognostic factors of metastatic pancreatic tumor. METHODS: The clinical data of 18 metastatic pancreatic tumors were retrospectively analyzed. The primary foci of these 18 patients included: 8 lung cancer, 2 gastric cancer, and malignant histiocytoma, melanoma, rectal cancer, thyroid cancer, renal cell carcinoma, esophageal carcinoma, liver cancer and ovarian cancer each. RESULTS: All these 18 patients harboring metastatic pancreatic tumor did not show any specific symptoms but were frequently found to have a solitary (14 cases) or multiple (4 cases) homogeneous and hypodense nodules on CT scan without any enhancement except one metastatic renal cell carcinoma. The diagnosis was cytologically confirmed in 14 patients by fine needle aspiration biopsy guided by CT or ultrasonography, and diagnosed by postoperative pathology in the other 4 patients. After receiving combined modality treatment, their survival time was 8 to 38 months with an average of 19 months. CONCLUSION: Metastatic pancreatic tumors are rare and give no specific symptom or image finding. Selection of appropriate combined modality treatment according to the type of primary focus is very important for the management.

[Clinicopathological characteristics and prognosis of remnant stomach cancer--report of 45 cases].

OBJECTIVE: To investigate the clinicopathological characteristics and prognostic factors of remnant stomach cancer. METHODS: The clinicopathological and prognosis data of 45 patients with remnant stomach cancer were retrospectively analyzed. RESULTS: The remnant stomach cancer are likely to develop in males with a ratio of male to female: 44:1. Their initial operation modes of these patients were Billroth II subtotal gastrectomy in 40 patients, Billroth I subtotal gastrectomy in 4 and proximal subtotal gastrectomy in 1. The interval from the initial operation to the diagnosis of remnant stomach cancer was 5 to 42 years with an average of 23 years. Of these 45 patients, 28 had lesion at anastomotic site, 9 in the gastric cardia and 8 in other locations; 19 had radical resection, 16 palliative resection and 10 exploration alone except one who had an anastomosis of remnant stomach with the jejunum. The histology types included: 1 un-differentiated adenocarcinoma, 36 poorly-differentiated adenocarcinoma, 7 moderately-differentiated adenocarcinoma and 1 well-differentiated adenocarcinoma. The 1-, 3-, 5-year survival rates of patients with radical resection were significantly better than those treated with palliative resection, which was 100% vs. 62.5%, 78.8% vs. 25%, 47.2% vs. 0, respectively (P < 0.05). All ten patients without resection died within 2 years with an average survival time of 12 months. The 5-year survival rate of stage I, II, III and IV was 100%, 75%, 17.8% and 0, respectively (P < 0.05). CONCLUSION: Remnant stomach cancer prevalently occurs in the male usually 10 years after Birroth II gastrectomy. The lesions is mainly located at anastomotic site. Poorly-differentiated adenocarcinoma is found to be the prevalent histological type of advanced remnant stomach cancer. The prognosis of remnant stomach cancer is correlated with pTNM stage and whether having been treated with complete resection or not. Patients with early remnant stomach cancer may survive for a long time if radical resection can be done.