Neuroinvasive Bacillus cereus Infection in Immunocompromised Hosts: Epidemiologic Investigation of 5 Patients With Acute Myeloid Leukemia.

Background: Bacillus cereus is a ubiquitous gram-positive rod-shaped bacterium that can cause sepsis and neuroinvasive disease in patients with acute leukemia or neutropenia. Methods: A single-center retrospective review was conducted to evaluate patients with acute leukemia, positive blood or cerebrospinal fluid test results for B cereus, and abnormal neuroradiographic findings between January 2018 and October 2022. Infection control practices were observed, environmental samples obtained, a dietary case-control study completed, and whole genome sequencing performed on environmental and clinical Bacillus isolates. Results: Five patients with B cereus neuroinvasive disease were identified. All patients had acute myeloid leukemia (AML), were receiving induction chemotherapy, and were neutropenic. Neurologic involvement included subarachnoid or intraparenchymal hemorrhage or brain abscess. All patients were treated with ciprofloxacin and survived with limited or no neurologic sequelae. B cereus was identified in 7 of 61 environmental samples and 1 of 19 dietary protein samples-these were unrelated to clinical isolates via sequencing. No point source was identified. Ciprofloxacin was added to the empiric antimicrobial regimen for patients with AML and prolonged or recurrent neutropenic fevers; no new cases were identified in the ensuing year. Conclusions: B cereus is ubiquitous in the hospital environment, at times leading to clusters with unrelated isolates. Fastidious infection control practices addressing a range of possible exposures are warranted, but their efficacy is unknown and they may not be sufficient to prevent all infections. Thus, including B cereus coverage in empiric regimens for patients with AML and persistent neutropenic fever may limit the morbidity of this pathogen.

Expression of AKT and p-AKT protein in lung adenocarcinoma and its correlation with PD-L1 protein and prognosis.

BACKGROUND: The PI3K/AKT/mTOR signaling pathway were significantly associated with EGFR mutation in lung adenocarcinoma (LUAD), but its correlation with PD-L1 protein and prognosis are not clear. The aim of this study was to evaluate the expression of AKT and phosphorylated AKT (p-AKT) in LUAD and its correlation with programmed death ligand-1 (PD-L1); and to analyze the factors affecting LUAD prognosis. METHODS: The expression of AKT, p-AKT, and PD-L1 was examined using immunohistochemistry in LUAD tissues from 110 patients who underwent surgical treatment. RESULTS: AKT protein expression was examined in 64.5% (71/110) of the LUAD samples, and p-AKT protein expression was examined in 44.5% (49/110) of the LUAD samples. The positive rate of PD-L1 at TC1/2/3 was 38.2% (42/110). AKT and p-AKT expression was significantly associated with epidermal growth factor receptor (EGFR) mutation (P=0.016, P=0.014 respectively). Pearson's correlation analysis indicated a negative correlation of p-AKT with PD-L1 protein (P=0.022). Out of the 62 patients with EGFR mutation, the expression of PD-L1 was negatively correlated with that of p-AKT protein (P=0.032). The expressions of AKT and p-AKT were not associated with prognosis. Multivariate analysis showed that tumor-node-metastasis (TNM) stage (P=0.013) and differentiation (P=0.046) were independent prognostic factors for overall survival. CONCLUSIONS: PI3K/AKT/mTOR in the downstream pathway of EGFR may negatively regulate the expression of PD-L1, which may partly explain why patients with EGFR mutation respond poorly to PD-1/PD-L1 inhibitors.

A Transcriptome Analysis: Various Reasons of Adverse Pregnancy Outcomes Caused by Acute Toxoplasma gondii Infection.

BACKGROUND: Toxoplasma gondii (T. gondii) is an obligate intracellular parasite, which can affect the pregnancy outcomes in infected females by damaging the uterus, and the intrauterine environment as well as and the hypothalamus resulting in hormonal imbalance. However, the molecular mechanisms underlying the parasite-induced poor pregnancy outcomes and the key genes regulating these mechanisms remain unclear. Therefore, this study aimed to analyze the gene expression in the mouse's uterus following experimentally-induced acute infection with T. gondii RH strain. Three groups of female mice were intraperitoneally injected with tachyzoites as follow; 3 days before pregnancy (FBD6), after pregnancy (FAD6), and after implantation (FID8) as the experimental groups. Another corresponding three groups served as control, were injected with normal saline at the same time. Transcriptome analysis of the total RNA extracted from both infected and non-infected mouse uterus samples was performed using RNA sequencing (RNA-Seq). RESULTS: The three experimental groups (FBD6, FAD6, and FID8) had a total of 4,561, 2,345, and 2,997 differentially expressed genes (DEGs) compared to the controls. The significantly upregulated and downregulated DEGs were 2,571 and 1,990 genes in FBD6, 1,042 and 1,303 genes in FAD6 and 1,162 and 1,835 genes in FID8 group, respectively. The analysis of GO annotation, and KEGG pathway showed that DEGs were mainly involved in anatomical structure development, transport, cell differentiation, embryo development, hormone biosynthetic process, signal transduction, immune system process, phagosome, pathways in cancer, and cytokine-cytokine receptor interaction pathways. CONCLUSION: T. gondii infection can induce global transcriptomic changes in the uterus that may cause pregnancy hypertension, destruct the intrauterine environment, and hinder the normal development of placenta and embryo. Our results may help to understand the molecular mechanisms of the acute T. gondii infection, which could promote the development of new therapeutics or prophylactics for toxoplasmosis in pregnancy.

Novel nor-monoterpenoid indole alkaloids inhibiting glioma stem cells from fruits of Alstonia scholaris.

BACKGROUND: Glioblastoma multiforme (GBM) is a highly aggressive and frequently recurrent malignant brain tumor, and to date, the clinically effective drugs against GBM remain scarce. Natural products play an important role in drug discovery, and might be the resource of antitumor agents for GSCs. Alstonia scholaris (L.) R. Br. is rich in monoterpenoid indole alkaloids (MIAs) and used extensively for treatment of tumor in the traditional medicine system of Asia. PURPOSE: To search for new MIAs with antitumor activity against glioma stem cells from clinical patients and explore their mechanism. METHODS: Compounds were obtained from the fruits of A. scholaris by chromatographic separation, including silica gel, Sephadex LH-20 and recrystallization. Their structures were elucidated by the use of UV, IR, NMR and MS spectra. The antitumor activity of the compounds against the glioma stem cells (GSC-3#, GSC-12#, GSC-18#) were investigated by phenotypic screening and MTS assays. Cell proliferation assay by BrdU immunofluorescence staining, and apoptosis assay by cleaved-caspase-3 immunofluorescence staining and real-time PCR assay. The soft-agar clonal formation assay was performed to determine the antitumor efficacy of the compounds in vitro. RESULTS: Two new nor-monoterpenoid indole alkaloids were isolated from the fruits of A. scholaris. They exhibited selective antitumor activity against glioma stem cells (GSC-3#, GSC-12#, GSC-18#) with IC50 values of 15-25 µg/ml. Furthermore, they inhibited GSCs proliferation, induced GSCs apoptosis by increasing the expression of TNF-α and cleavage of caspase-3, and significantly damaged colony forming capacity of GSCs. CONCLUSION: New nor-monoterpenoid indole alkaloids from the fruits of A. scholaris provide new type promising molecule for the selective killing of human glioma stem cells.

Effects of indole alkaloids from leaf of Alstonia scholaris on post-infectious cough in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Leaf of Alstonia scholaris (L.) R. Br. (Apocynaceae), a wide used ethic-medicine in many Asia and Africa counties, has also been recorded as the common traditional Chinese medicine for treatment of illnesses in respiratory system by Dai people. AIM OF THE STUDY: To provide experimental data of clinical adaption of total indole alkaloids (TA) from leaf of A. scholaris for treating post-infectious cough in phase II clinical trial. MATERIALS AND METHODS: To model post-infectious cough, all animals except control group were instilled intra-tracheal with lipopolysaccharide (LPS) (80 µg/50 µL/mouse), followed by subsequent exposure to cigarette smoke (CS) for 30 min per day for a total of 30 days. Mice were orally given TA at dose of 10, 25, 50 mg/kg, and four main alkaloids (Sch: scholaricine, Epi: 19-epischolaricine, Val: vallesamine, Pic: picrinine) once daily. Cellular infiltration was assessed in the broncho-alveolar lavage fluid (BALF). Expression of interleukin-6 (IL-6) and C-reactive protein (CRP) in the serum was determined, the superoxide dismutase (SOD) activity as well as malondialdehyde (MDA) content in the serum and homogenate were examined. Finally, histopathological examination in the lungs was assessed by H. E. staining. RESULTS: After administration of TA and four major alkaloids respectively, the symptoms of cough in mice were obviously attenuated. Total white blood cells (WBC) and neutrophils (NEU) amounts in BALF were reduced obviously and the pathological damage of lung was also attenuated. There was also significant reduction in IL-6, CRP, MDA and a marked improvement in SOD. CONCLUSIONS: The efficacy of indole alkaloids against post-infectious cough (PIC) was shown in the down-regulation of inflammatory cells, cytokines, and the balance of antioxidants. What's more, the pharmacological effects of TA were better than single indole alkaloid, which might be related to the synergic effect of four major alkaloids.

Unprecedented sugar bridged bisindoles selective inhibiting glioma stem cells.

Unlike reported bisindoles linked by single bond directly, alstoniasidines A (1) and B (2), from Alstonia scholaris featuring unprecedented skeleton with two indole moieties bridged by a sugar, represented a novel bisindole type having strictosamide-glucopyranose-picraline scaffold. Both compounds exhibited selective cytotoxicity against human glioma stem cells (GSCs) and induced caspase-3 dependent extrinsic apoptosis by increasing the expression of interleukin 1 (IL-1), tumor necrosis factor (TNF-α), and the cleaved caspase-3, while damaged the unlimited proliferation and self-renewal capacity of GSCs. This finding might provide new type of leads for the selective killing of human glioma stem cells.

[Effect of abdominal acupuncture therapy on the endocrine and metabolism in obesity-type polycystic ovarian syndrome patients].

OBJECTIVE: To observe the effect of abdominal acupuncture on the endocrine and metabolic level in obesity-type polycystic ovarian syndrome (PCOS) patients. METHODS: Eighty-six PCOS patients were randomly and equally divided into medication group and abdominal acupuncture group. Patients of medication group were treated with metformin (250 mg/time, t.i. d. in the 1st week, and 500 mg/time, t.i.d. thereafter) for 6 months,and those of abdominal acupuncture group were treated by abdominal acupuncture [Zhongwan (CV 12), Liangmen (ST 21), etc., once daily for 6 months]. Changes of the body height, body Mass index (BMI), waist-hip ratio (WHR), Ferriman-Galleey score (FGS), menstrual frequency (MF) and ovarian volume (OV) were determined. Serum luteotrophic hormone (LH), free testosterone (T), follicle-stimulating hormone (FSH) contents were detected with radioimmunoassay. Fasting blood glucose (FBG), fasting insulin (FIN), total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), Homa insulin resistance index (IRI) were detected with chromatometry respectively. RESULTS: After the treatment, BMI, WHR, FGS and OV were reduced significantly in both medication and abdominal acupuncture groups (P < 0.05), while MF of the two groups increased evidently (P < 0.05), and the effects of abdominal acupuncture group were significantly superior to those of medication group in down-regulating BMI, WHR and upregulating MF (P < 0.05). Regarding the reproductive hormons, serum LH, LH/FSH and T levels in the two groups decreased significantly (P< 0.05), and the effect of abdominal acupuncture was superior to that of medication group in reducing serum T level (P < 0.05). Following the treatment, FBG, BG and FIN and INS contents 2 h after meal,and Homa IR in both medication and abdominal acupuncture groups all decreased considerably (P < 0.05), but without significant differences between them (P > 0.05). Regarding the blood lipid levels after the treatment, serum TC, TG, and LDL-C levels of the two groups decreased significantly (P < 0.05), while serum HDL-C level increased remarkably (P<0.05), without significant differences between the two groups in these indexes (P > 0.05). CONCLUSION: Abdominal acupuncture treatment can improve the endocrine and metabolic function of patients with obesity-type PCOS.

Ruptured pseudoaneurysm of the external iliac artery in an advanced cervical cancer patient treated by endovascular covered stent placement.

The formation of pseudoaneurysms in patients with gynecologic malignancies is rare. We describe a patient with locally advanced cervical cancer who had life-threatening rectal bleeding due to a ruptured pseudoaneurysm of the right external iliac artery, which was successfully treated by emergent endovascular covered stent placement. This 56-year-old woman had received concurrent chemoradiation, salvage hysterectomy and systemic chemotherapy for advanced cervical cancer. About 25 months after her diagnosis of cervical cancer, she suffered from acute life-threatening rectal bleeding. Angiography revealed active extravasation from a pseudoaneurysm of the right external iliac artery. A covered stent was placed across the pseudoaneurysm via an endovascular approach to stop the bleeding. The patient recovered well without any sequelae. We believe that this technique might also be useful in other irradiated gynecologic cancer patients, especially when direct surgical repair is difficult to perform due to pelvic irradiation or tumor recurrence.