Complete Genome Sequences of Klebsiella michiganensis and Citrobacter farmeri, KPC-2-Producers Serially Isolated from a Single Patient

Carbapenemase-producing Enterobacterales, including KPC-2 producers, have become a major clinical problem. During an outbreak in Quebec City, Canada, KPC-2-producing Klebsiella michiganensis and Citrobacter farmeri were isolated from a patient six weeks apart. We determined their complete genome sequences. Both isolates carried nearly identical IncN2 plasmids with blaKPC-2 on a Tn4401b element. Both strains also carried IncP1 plasmids, but that of C. farmeri did not carry a Beta-lactamase gene, whereas that of K. michiganensis carried a second copy of blaKPC-2 on Tn4401b. These results suggest recent plasmid transfer between the two species and a recent transposition event.

INNV-15. PROTEIN TYPING AND MRNA ANALYSIS OF CIRCULATING EXOSOMES FOR GLIOBLASTOMA THERAPY USING PLASMONIC-ENHANCED INTEGRATED MAGNETO-ELECTROCHEMICAL SENSOR

Monitoring of drug efficacy in glioblastoma multiforme (GBM) is a major clinical problem. Glioblastomas shed large quantities of exosomes into the circulation. Although these hold promise as potential biomarkers of therapeutic response, their identification and quantification remain challenging. Recently, we develop a highly sensitive and rapid analytical technique for profiling circulating exosomes directly from serum plasma of patients with glioblastoma. Exosomes are labeled with target-specific metal nanoparticles and detected by a miniaturized integrated magneto-electrochemical sensing system. Compared with current methods, this integrated system has a much higher detection sensitivity and can differentiate GBM exosomes from nontumor host cell–derived exosomes. We also show that circulating GBM exosomes can be used to analyze primary tumor mutations and as a predictive metric of treatment-induced changes. This platform could provide both an early indicator of drug efficacy and a potential molecular stratifier for human clinical trials.

The Role of the Immune Response in Brain Metastases: Novel Imaging Biomarkers for Immunotherapy

Brain metastases are a major clinical problem, and immunotherapy offers a novel treatment paradigm with the potential to synergize with existing focal therapies like surgery and radiosurgery or even replace them in future. The brain is a unique microenvironment structurally and immunologically. The immune response is likely to be crucial to the adaptation of systemic immune modulating agents against this disease. Imaging is frequently employed in the clinical diagnosis and management of brain metastasis, so it is logical that brain imaging techniques are investigated as a source of biomarkers of the immune response in these tumors. Current imaging techniques in clinical use include structural MRI (post-contrast T1W sequences, T2, and FLAIR), physiological sequences (perfusion- and diffusion-weighted imaging), and molecular imaging (MR spectroscopy and PET). These are reviewed for their application to predicting and measuring the response to immunotherapy in brain metastases.

Biomarkers of acute kidney injury: time to learn from implementation

Acute kidney injury (AKI) is a major clinical problem in the community and in hospital, with hospital-acquired AKI reported in about 20% of adult and 30% of paediatric admissions.

Targeted Inhibition of FTO Demethylase Protects Mice Against LPS-Induced Septic Shock by Suppressing NLRP3 Inflammasome

Sepsis refers to the systemic inflammatory response syndrome caused by infection. It is a major clinical problem and cause of death for patients in intensive care units worldwide. The Fat mass and obesity-related protein (FTO) is the primary N6-methyladenosine demethylase. However, the role of FTO in the pathogenesis of inflammatory diseases remains unclear. We herein show that nanoparticle-mediated Fto-siRNA delivery or FTO inhibitor entacapone administration dramatically inhibited macrophage activation, reduced the tissue damage and improved survival in a mouse model of LPS-induced endotoxic shock. Importantly, ablation of FTO could inhibit NLRP3 inflammasome through FoxO1/NF-κB signaling in macrophages. In conclusion, FTO is involved in inflammatory response of LPS-induced septic shock and inhibition of FTO is promising for the treatment of septic shock.

Dissemination of Carbapenemases (OXA-48, NDM and VIM) Producing Enterobacteriaceae Isolated from the Mohamed VI University Hospital in Marrakech, Morocco

The emergence and spread of carbapenem-resistant Enterobacteriaceae (CRE) represent a major clinical problem and raise serious health concerns. The present study aimed to investigate and ascertain the occurrence of CRE among hospitalized patients of Mohamed VI University Hospital, Marrakech, Morocco. Biological samples were collected over a one-year period (2018). The bacterial isolates were identified by MALDI-TOF-MS. Antibiotic susceptibility testing was performed using disc diffusion and Etest. The modified Hodge test and combined disc diffusion test were used for phenotypic detection. CRE hydrolyzing enzyme encoding genes: blaOXA-48, blaKPC, blaIMP, blaVIM, and blaNDM were characterized by PCR and DNA sequencing. In total, 131 non-duplicate CRE clinical strains resistant to Ertapenem were isolated out of 1603 initial Enterobacteriaceae. Klebsiella pneumoniae was the most common species (59%), followed by Enterobacter cloacae (24%), E. coli (10%), Citrobacter freundii (3%), Klebsiellaoxycota (2%), Serratia marcescens (1%), and Citrobacter braakii (1%). Of these, 56.49%, 21.37%, 15.27%, 3.38%, and 3.05% were collected from blood, urine, pus, catheters and respiratory samples, respectively. Approximately 85.5% (112/131) of the isolates were carbapenemase producers (40 blaOXA-48, 27 blaNDM, 38 blaOXA-48 + blaNDM and 7 blaVIM). All metallo-β-lactamases isolates were NDM-1 and VIM-1 producers. This is the first documentation of blaOXA-48 genes from C. freundii and C. braakii in Morocco.

Feasibility of ultrathin endoscope for esophageal endoscopic submucosal dissection

Background and study aims Endoscopic submucosal dissection (ESD) is widely performed for superficial esophageal cancer, but stricture after extensive resection is a major clinical problem. Using an ultrathin endoscope would enable endoscopists to approach lesions beyond the stricture. We evaluated the feasibility of an ultrathin endoscope for esophageal ESD. Methods To perform ESD with an ultrathin endoscope, we developed a transparent hood and ESD knife. A total of 24 esophageal ESDs were performed by two endoscopists with excised and live porcine esophaguses. A GIF-Q260 J and Dual knife were used in the conventional group and the GIF-XP260NS and a newly developed knife were used in the ultrathin group. En bloc resection rates, perforation rates, and procedure times were compared. Results All 24 lesions were resected en bloc without perforation. The mean procedure time was longer in the ultrathin group, although not significantly so (274.3 ± 81.8 s vs 435.8 ± 313.9 s, respectively; P = 0.22). Conclusion Although the procedure time was longer in the ultrathin group, en bloc resection was performed without any perforation. The findings indicate that esophageal ESD with an ultrathin endoscope is feasible.

Plasticity in the Hippocampus, Neurogenesis and Drugs of Abuse

Synaptic plasticity in the hippocampus assists with consolidation and storage of long-lasting memories. Decades of research has provided substantial information on the cellular and molecular mechanisms underlying synaptic plasticity in the hippocampus, and this review discusses these mechanisms in brief. Addiction is a chronic relapsing disorder with loss of control over drug taking and drug seeking that is caused by long-lasting memories of drug experience. Relapse to drug use is caused by exposure to context and cues associated with the drug experience, and is a major clinical problem that contributes to the persistence of addiction. This review also briefly discusses some evidence that drugs of abuse alter plasticity in the hippocampus, and that development of novel treatment strategies that reverse or prevent drug-induced synaptic alterations in the hippocampus may reduce relapse behaviors associated with addiction.

A Panoramic view of most commonly used Regimenal Modalities (Tadabeer) for joint pain in Unani System of Medicine: A Critical Review

Pain in joints (Waja ul Mafasil) is a major clinical problem that may or may not be associated with inflammation. Researchers and Clinicians are rigorously working to find out the best treatment modality in the management of joint pain. Unani physicians claimed the management of various joint disorders with the help of several Tadabeer. The objective of this critical review is to address the claims of Unani physicians and clinical studies conducted on the efficacy of Dalk or Hijama in the management of joint pain. Classical Unani literature, peer-reviewed journal articles and RCTs that predominantly focused on the use of regimenal modalities (Hijama and Dalk) in the joint pain were included in this review. Several published studies claiming the effect of Dalk and Hijama by Unani physicians, showing significant improvement, were included along with the literature. Various published clinical trials showed the effect of Dalk and Hijama in the management of joint pain, though, the effect showed by some clinical trials was short term. Hence, rigorous, controlled, randomized, blinded, and long duration follow up studies on large sample size are to be conducted by trained clinicians or researchers to establish the efficacy of Dalk or Hijama in the management of musculoskeletal disorders (MSDs). Keywords: Dalk; Hijama; Waja-ul-Mafasil; Joint Pain; Musculoskeletal Disorders; Unani

Hsp70 acts as a fine-switch that controls E3 ligase CHIP-mediated TAp63 and ΔNp63 ubiquitination and degradation

The major clinical problem in human cancer is metastasis. Metastases are the cause of 90% of human cancer deaths. TAp63 is a critical suppressor of tumorigenesis and metastasis. ΔNp63 acts as a dominant-negative inhibitor to block the function of p53 and TAp63. Although several ubiquitin E3 ligases have been reported to regulate p63 stability, the mechanism of p63 regulation remains partially understood. Herein, we show that CHIP, an E3 ligase with a U-box domain, physically interacts with p63 and promotes p63 degradation. Notably, Hsp70 depletion by siRNA stabilizes TAp63 in H1299 cells and destabilizes ΔNp63 in SCC9 cells. Loss of Hsp70 results in a reduction in the TAp63-CHIP interaction in H1299 cells and an increase in the interaction between ΔNp63 and CHIP in SCC9 cells. Our results reveal that Hsp70 acts as a molecular switch to control CHIP-mediated ubiquitination and degradation of p63 isoforms. Furthermore, regulation of p63 by the Hsp70-CHIP axis contributes to the migration and invasion of tumor cells. Hence, our findings demonstrate that Hsp70 is a crucial regulator of CHIP-mediated ubiquitination and degradation of p63 isoforms and identify a new pathway for maintaining TAp63 or ΔNp63 stability in cancers.