Prolyl isomerase cyclophilin A regulation of Janus-activated kinase 2 and the progression of human breast cancer

The activation of the Janus-activated kinase 2 (Jak2) tyrosine kinase following ligand binding has remained incompletely characterized at the mechanistic level. We report that the peptidyl-prolyl isomerase (PPI) cyclophilin A (CypA), which is implicated in the regulation of protein conformation, is necessary for the prolactin (PRL)-induced activation of Jak2 and the progression of human breast cancer. A direct correlation was observed between the levels or activity of CypA and the extent of PRL-induced signaling and gene expression. Loss of PRLr-CypA binding, following treatment with the PPI inhibitor cyclosporine A (CsA), or overexpression of a dominant-negative PRLr mutant (P334A) resulted in a loss of PRLr/Jak2-mediated signaling. In vitro, CsA treatment of breast cancer cells inhibited their growth, motility, invasion, and soft agar colony formation. In vivo, CsA treatment of nude mice xenografted with breast cancer cells induced tumor necrosis and completely inhibited metastasis. These studies reveal that a CypA-mediated conformational change within the PRLr/Jak2 complex is required for PRL-induced transduction and function and indicate that the inhibition of prolyl isomerases may be a novel therapeutic strategy in the treatment of human breast cancer.     

In vivo selection of hematopoietic progenitor cells and temozolomide dose intensification in rhesus macaques through lentiviral transduction with a drug resistance gene

Major limitations to gene therapy using HSCs are low gene transfer efficiency and the inability of most therapeutic genes to confer a selective advantage on the gene-corrected cells. One approach to enrich for gene-modified cells in vivo is to include in the retroviral vector a drug resistance gene, such as the P140K mutant of the DNA repair enzyme O⁶-methylguanine-DNA methyltransferase (MGMT*). We transplanted 5 rhesus macaques with CD34⁺ cells transduced with lentiviral vectors encoding MGMT* and a fluorescent marker, with or without homeobox B4 (HOXB4), a potent stem cell self-renewal gene. Transgene expression and common integration sites in lymphoid and myeloid lineages several months after transplantation confirmed transduction of long-term repopulating HSCs. However, all animals showed only a transient increase in gene-marked lymphoid and myeloid cells after O⁶-benzylguanine (BG) and temozolomide (TMZ) administration. In 1 animal, cells transduced with MGMT* lentiviral vectors were protected and expanded after multiple courses of BG/TMZ, providing a substantial increase in the maximum tolerated dose of TMZ. Additional cycles of chemotherapy using 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU) resulted in similar increases in gene marking levels, but caused high levels of nonhematopoietic toxicity. Inclusion of HOXB4 in the MGMT* vectors resulted in no substantial increase in gene marking or HSC amplification after chemotherapy treatment. Our data therefore suggest that lentivirally mediated gene transfer in transplanted HSCs can provide in vivo chemoprotection of progenitor cells, although selection of long-term repopulating HSCs was not seen.     

A prospective cohort study of intrathecal versus epidural analgesia for patients undergoing hepatic resection

Background

The aim of this prospective observational study was to compare peri/post-operative outcomes of thoracic epidural analgesia (TEA) versus intrathecal morphine and fentanyl patient-controlled analgesia (ITM+fPCA) for patients undergoing a hepatic resection (HR).

Method

Patients undergoing elective, one-stage, open HR for benign and malignant liver lesions, receiving central neuraxial block as part of the anaesthetic, in a high-volume hepato-pancreato-biliary unit, were included in the study. The primary outcome measure was post-operative length of stay (LoS).

Results

A total of 73 patients (36 TEA and 37 ITM+fPCA) were included in the study. The median (IQR) post-operative LoS was 13 (11–15) and 11 (9–13) days in the TEA and ITM+fPCA groups, respectively (P = 0.011). There was significantly lower median intra-operative central venous pressure (P < 0.001) and blood loss (P = 0.017) in the TEA group, and a significant reduction in the time until mobilization (P < 0.001), post-operative intra-venous fluid/vasopressor requirement (P < 0.001/P = 0.004) in the ITM+fPCA group. Pain scores were lower at a clinically significant level 12 h post-operatively in the TEA group (P < 0.001); otherwise there were no differences out to day five. There were no differences in quality of recovery or postoperative morbidity/mortality between the two groups.

Conclusion

ITM+fPCA provides acceptable post-operative outcomes for HR, but may also increase the incidence of intra-operative blood loss in comparison to TEA.     

Studies on the hypoglycemic effects of Murraya paniculata Linn. extract on alloxan-induced oxidative stress in diabetic and non-diabetic models

ObjectiveTo evaluate the effect of extract of Murraya paniculata Linn. (Family – Rutaceae) on blood glucose, cholesterol, triglyceride and lipid level and antioxidant status in alloxan induced diabetic and non-diabetic rats.MethodsHydro-alcoholic extract of M. paniculata leaves (100, 200 and 400 mg/kg) was administered orally for 14 days and its effect on blood glucose, cholesterol, triglycerides and lipid level were estimated in serum. Liver free radical (lipid peroxidation, LPO) and antioxidant (Super oxide dismutase, SOD; catalase, CAT; and reduced glutathione peroxidase, GPx) were also measured after 14 days treatment with extract. Glucose level in non-diabetic rats was estimated after 21 days treatment with M. paniculata extract.ResultsOral administrations of M. paniculata extract (100, 200 and 400 mg/kg) for 14 days significantly reduced the levels of blood glucose, cholesterol, and triglyceride and lipid level. Liver free radical (LPO) significantly reduced and antioxidants (SOD, CAT and GPx) status significantly increase after 14 days treatment of extract in diabetic rats. M. paniculata 200 and 400 mg/kg significantly decrease glucose level in non-diabetic rats after 21 day and caused hypoglycemia in normal rats.ConclusionsM. paniculata leaves extract posses hypoglycemic effect in oxidative stress condition and also in non-diabetic condition. Hypoglycemic action may be by potentiating of the insulin effect by increasing either the pancreatic secretion of insulin from beta cells of islets of langerhans or its release from the bound form. M. paniculata could be a potential source of hypoglycemic agent with antioxidant properties.     

Current State of Evidence for Neuroimaging Paradigms in Management of Acute Ischemic Stroke

Stroke is the chief differential diagnosis in patient presenting to the emergency room with abrupt onset focal neurological deficits. Neuroimaging, including non-contrast computed tomography (CT), magnetic resonance imaging (MRI), vascular and perfusion imaging, is a cornerstone in the diagnosis and treatment decision-making. This review examines the current state of evidence behind the different imaging paradigms for acute ischemic stroke diagnosis and treatment, including current recommendations from the guidelines. Non-contrast CT brain, or in some centers MRI, can help differentiate ischemic stroke and intracerebral hemorrhage (ICH), a pivotal juncture in stroke diagnosis and treatment algorithm, especially for early window thrombolytics. Advanced imaging such as MRI or perfusion imaging can also assist making a diagnosis of ischemic stroke versus mimics such as migraine, Todd's paresis, or functional disorders. Identification of medium-large vessel occlusions with CT or MR angiography triggers consideration of endovascular thrombectomy (EVT), with additional perfusion imaging help identify salvageable brain tissue in patients who are likely to benefit from reperfusion therapies, particularly in the ≥6 h window. We also review recent advances in neuroimaging and ongoing trials in key therapeutic areas and their imaging selection criteria to inform the readers on potential future transitions into use of neuroimaging for stroke diagnosis and treatment decision making. ANN NEUROL 2024;95:1017–1034     

Underuse of screening mammography by family physicians

Although the American College of Radiology, the National Cancer Institute, and the American Cancer Society recommend screening mammography for women more than 40 years old, there is little compliance with these recommendations. Primary-care physicians are often reluctant to refer patients for the procedure, whereas the patients are usually willing to undergo the procedure. This survey documents the underuse of screening mammography by family physicians who are members of the Michigan Academy of Family Physicians. The underuse of mammography by this physician sample was due to two main factors: The physicians perceived far more disadvantages than advantages with mammography and perceived problems (with, e.g., equipment, effectiveness, and patient acceptance) as pervasive. To change the attitudes and referral behavior of family physicians, one must take into account the specific, negative perceptions of the procedure and place an emphasis on the initial referral, since subsequent referrals are easier to implement.     

Cervical radiculopathy: value of oblique MR imaging

Eighteen patients with cervical radiculopathy were entered into a prospective study to compare the accuracy of surface coil magnetic resonance (MR) imaging with that of metrizamide myelography and computed tomography (CT) with metrizamide. All MR studies included tailored axial and oblique images as well as routine sagittal images. All imaging studies were evaluated for topography and type of disease. Nine of 18 patients subsequently underwent cervical surgery with an anterior interbody approach at 11 levels. The surface coil MR findings concerning disease topography and type concurred with the surgical findings at nine of 11 levels (82%). At three levels, the oblique view added important information not available on the sagittal images or clarified changes seen on the axial images. Metrizamide myelography with CT metrizamide myelography had findings concurrent with surgical findings at ten of 11 levels (91%).