Genomic analysis of antibiotic resistance for Acinetobacter baumannii in a critical care center

AimAcinetobacter baumannii is commonly associated with outbreaks and antibiotic‐resistant nosocomial infection. This study aimed to determine the relationship between antibiotic resistance and genotypes of A. baumannii.MethodsA study was undertaken in the critical care center (CCC) of Juntendo University Urayasu Hospital (Urayasu, Japan) between January 2012 and September 2015. Antimicrobial susceptibility tests were carried out according to the Clinical and Laboratory Standards Institute guidelines. All A. baumannii isolates were verified to carry carbapenemase genes and the ISAba1 element using polymerase chain reaction. The genetic relationship of all A. baumannii isolates was determined by pulsed‐field gel electrophoresis and multilocus sequence typing.ResultsDuring the study period, 1634 patients were admitted to the CCC. Acinetobacter baumannii was detected in 43 patients (average age, 58 ± 19 years; 67.4% men). Six patients were determined to be extensively drug‐resistant A. baumannii and 21 patients determined to be multidrug‐resistant A. baumannii. Antimicrobial susceptibility linked genotypes of A. baumannii. Molecular characterization by pulsed‐field gel electrophoresis and multilocus sequence typing showed that closely related clones of A. baumannii had spread in the CCC.ConclusionResistance to antimicrobial drugs was significantly associated with certain A. baumannii genotypic types and molecular types. Thus, we might be able to predict whether the genotype has spread in the CCC or not when the susceptibility is examined, facilitating the appropriate isolation of patients

Rechallenge with First-Line Platinum Chemotherapy for Sensitive-Relapsed Small-Cell Lung Cancer

Background: Sensitive-relapsed small-cell lung cancer (SCLC) is thought to be sensitive to chemotherapy; therefore, second-line chemotherapy is recommended. Although platinum rechallenge is performed in the second-line chemotherapy for sensitive-relapsed SCLC, it remains unclear whether such a strategy is effective. Methods: We retrospectively analyzed the outcome of rechallenge chemotherapy for sensitive-relapsed SCLC. The endpoints of this study were progression-free survival from the time of relapse (PFS-Re) and overall survival from the time of relapse (OS-Re). We also compared the toxicity profile of rechallenge chemotherapy to that of first-line chemotherapy. Results: Of the 133 SCLC patients who received first-line treatment, 20 patients satisfied the definition of sensitive relapse and received rechallenge chemotherapy. Combined carboplatin and etoposide was the most commonly used rechallenge regimen, and 17 (85%) received it at a reduced dose due to hematological toxicity during the first-line treatment. Median PFS-Re and OS-Re were 4.5 months (95% CI: 3.5–5.4) and 10.5 months (95% CI: 7.9–13.0), respectively. There was no association between dose adjustment and survival. The frequency of hematologic toxicity tended to be lower with rechallenge than first-line treatment. The incidence of grade 3 febrile neutropenia decreased from 40% in first-line treatment to 15% in rechallenge. Conclusion: Platinum rechallenge could be a useful second-line option for sensitive-relapsed SCLC, having favorable efficacy and safety. Dose adjustment at rechallenge based on the toxicity profile during the first-line chemotherapy could reduce toxicity without weakening efficacy

Rechallenge with First-Line Platinum Chemotherapy for Sensitive-Relapsed Small-Cell Lung Cancer

Background: Sensitive-relapsed small-cell lung cancer (SCLC) is thought to be sensitive to chemotherapy; therefore, second-line chemotherapy is recommended. Although platinum rechallenge is performed in the second-line chemotherapy for sensitive-relapsed SCLC, it remains unclear whether such a strategy is effective. Methods: We retrospectively analyzed the outcome of rechallenge chemotherapy for sensitive-relapsed SCLC. The endpoints of this study were progression-free survival from the time of relapse (PFS-Re) and overall survival from the time of relapse (OS-Re). We also compared the toxicity profile of rechallenge chemotherapy to that of first-line chemotherapy. Results: Of the 133 SCLC patients who received first-line treatment, 20 patients satisfied the definition of sensitive relapse and received rechallenge chemotherapy. Combined carboplatin and etoposide was the most commonly used rechallenge regimen, and 17 (85%) received it at a reduced dose due to hematological toxicity during the first-line treatment. Median PFS-Re and OS-Re were 4.5 months (95% CI: 3.5–5.4) and 10.5 months (95% CI: 7.9–13.0), respectively. There was no association between dose adjustment and survival. The frequency of hematologic toxicity tended to be lower with rechallenge than first-line treatment. The incidence of grade 3 febrile neutropenia decreased from 40% in first-line treatment to 15% in rechallenge. Conclusion: Platinum rechallenge could be a useful second-line option for sensitive-relapsed SCLC, having favorable efficacy and safety. Dose adjustment at rechallenge based on the toxicity profile during the first-line chemotherapy could reduce toxicity without weakening efficacy

Spectral evolution of GRB 060904A observed with Swift and Suzaku -- Possibility of Inefficient Electron Acceleration

We observed an X-ray afterglow of GRB 060904A with the Swift and Suzaku satellites. We found rapid spectral softening during both the prompt tail phase and the decline phase of an X-ray flare in the BAT and XRT data. The observed spectra were fit by power-law photon indices which rapidly changed from $\Gamma = 1.51^{+0.04}_{-0.03}$ to $\Gamma = 5.30^{+0.69}_{-0.59}$ within a few hundred seconds in the prompt tail. This is one of the steepest X-ray spectra ever observed, making it quite difficult to explain by simple electron acceleration and synchrotron radiation. Then, we applied an alternative spectral fitting using a broken power-law with exponential cutoff (BPEC) model. It is valid to consider the situation that the cutoff energy is equivalent to the synchrotron frequency of the maximum energy electrons in their energy distribution. Since the spectral cutoff appears in the soft X-ray band, we conclude the electron acceleration has been inefficient in the internal shocks of GRB 060904A. These cutoff spectra suddenly disappeared at the transition time from the prompt tail phase to the shallow decay one. After that, typical afterglow spectra with the photon indices of 2.0 are continuously and preciously monitored by both XRT and Suzaku/XIS up to 1 day since the burst trigger time. We could successfully trace the temporal history of two characteristic break energies (peak energy and cutoff energy) and they show the time dependence of $\propto t^{-3} \sim t^{-4}$ while the following afterglow spectra are quite stable. This fact indicates that the emitting material of prompt tail is due to completely different dynamics from the shallow decay component. Therefore we conclude the emission sites of two distinct phenomena obviously differ from each other.Comment: 19 pages, 9 figures, accepted for publication in PASJ (Suzaku 2nd Special Issue

Psychiatric-disorder-related behavioral phenotypes and cortical hyperactivity in a mouse model of 3q29 deletion syndrome

3q29 microdeletion, a rare recurrent copy number variant (CNV), greatly confers an increased risk of psychiatric disorders, such as schizophrenia and autism spectrum disorder (ASD), as well as intellectual disability. However, disease-relevant cellular phenotypes of 3q29 deletion syndrome remain to be identified. To reveal the molecular and cellular etiology of 3q29 deletion syndrome, we generated a mouse model of human 3q29 deletion syndrome by chromosome engineering, which achieved construct validity. 3q29 deletion (Df/+) mice showed reduced body weight and brain volume and, more importantly, impaired social interaction and prepulse inhibition. Importantly, the schizophrenia-related impaired prepulse inhibition was reversed by administration of antipsychotics. These findings are reminiscent of the growth defects and neuropsychiatric behavioral phenotypes in patients with 3q29 deletion syndrome and exemplify that the mouse model achieves some part of face validity and predictive validity. Unbiased whole-brain imaging revealed that neuronal hyperactivation after a behavioral task was strikingly exaggerated in a restricted region of the cortex of Df/+ mice. We further elucidated the cellular phenotypes of neuronal hyperactivation and the reduction of parvalbumin expression in the cortex of Df/+ mice. Thus, the 3q29 mouse model provides invaluable insight into the disease-causative molecular and cellular pathology of psychiatric disorders

Differential gene expression profiles in neurons generated from lymphoblastoid B-cell line-derived iPS cells from monozygotic twin cases with treatment-resistant schizophrenia and discordant responses to clozapine

Schizophrenia is a chronic psychiatric disorder with complex genetic and environmental origins. While many antipsychotics have been demonstrated as effective in the treatment of schizophrenia, a substantial number of schizophrenia patients are partially or fully unresponsive to the treatment. Clozapine is the most effective antipsychotic drug for treatment-resistant schizophrenia; however, clozapine has rare but serious side-effects. Furthermore, there is inter-individual variability in the drug response to clozapine treatment. Therefore, the identification of the molecular mechanisms underlying the action of clozapine and drug response predictors is imperative. In the present study, we focused on a pair of monozygotic twin cases with treatment-resistant schizophrenia, in which one twin responded well to clozapine treatment and the other twin did not. Using induced pluripotent stem (iPS) cell-based technology, we generated neurons from iPS cells derived from these patients and subsequently performed RNA-sequencing to compare the transcriptome profiles of the mock or clozapine-treated neurons. Although, these iPS cells similarly differentiated into neurons, several genes encoding homophilic cell adhesion molecules, such as protocadherin genes, showed differential expression patterns between these two patients. These results, which contribute to the current understanding of the molecular mechanisms of clozapine action, establish a new strategy for the use of monozygotic twin studies in schizophrenia research

Similar survival benefits of a good response and stable disease to platinum-based chemotherapy in non-small cell lung cancer

The present study aimed to evaluate the similar survival benefits of a good response [complete response or partial response (CR/PR)] and stable disease (SD) to chemotherapy in non‑small cell lung cancer (NSCLC) patients in clinical practice. All 322 patients who were treated between 1999 and 2012 with first‑line platinum‑based chemotherapy were retrospectively analyzed. Tumor responses were classified according to the response evaluation criteria for solid tumors. A total of 67 (20.8%) patients experienced CR/PR and 165 (51.2%) achieved SD. There was no difference in progression‑free survival between the patients with CR/PR and those with SD (P=0.347). There was also no difference between the two groups with regard to overall survival time (P=0.878). In multivariate analysis, disease‑control (more than SD) was one of the favorable prognostic factors. In clinical practice, a survival benefit would be provided not only for the patients who have good response, but also for those with SD

Chronic expanding hematoma in the chest: A case report

Chronic expanding hematoma (CEH) is a rare disease that is usually present as a large solitary pulmonary nodule. CEHs are slow growing, but processes underlying their development remain unknown. The present study herein reports the case of a 76‑year‑old male patient with CEH and discusses a number of CEH cases published in the literature. The majority of these previously described patients were Asians. The CEH in the present case was not a successfully resected one, but the patient\u27s clinical course provided information concerning the natural history of the disease. During the clinical course, the patient underwent several chest computed tomography scans. For the present case report, the doubling time and volume change of the mass was calculated, which revealed that the lesion had an inconstant growth rate and that its onset was between 8.2‑11.0 years before the patient succumbed to this disease. Accumulation of knowledge about this rare disease will help to elucidate it further

Amplified EPOR/JAK2 Genes Define a Unique Subtype of Acute Erythroid Leukemia

ゲノム解析から急性赤白血病の変異プロファイルと治療標的を解明 --特定の遺伝子変異群の組み合わせと、特徴となる遺伝子の増幅が鍵--. 京都大学プレスリリース. 2022-08-05.Acute erythroid leukemia (AEL) is a unique subtype of acute myeloid leukemia characterized by prominent erythroid proliferation whose molecular basis is poorly understood. To elucidate the underlying mechanism of erythroid proliferation, we analyzed 121 AEL using whole-genome/exome and/or targeted-capture sequencing, together with transcriptome analysis of 21 AEL samples. Combining publicly available sequencing data, we found a high frequency of gains/amplifications involving EPOR/JAK2 in TP53-mutated cases, particularly those having >80% erythroblasts designated as pure erythroid leukemia (10/13). These cases were frequently accompanied by gains/amplifications of ERG/ETS2 and associated with a very poor prognosis, even compared with other TP53-mutated AEL. In addition to activation of the STAT5 pathway, a common feature across all AEL cases, these AEL cases exhibited enhanced cell proliferation and heme metabolism and often showed high sensitivity to ruxolitinib in vitro and in xenograft models, highlighting a potential role of JAK2 inhibition in therapeutics of AEL

The Japanese Clinical Practice Guideline for acute kidney injury 2016

Acute kidney injury (AKI) is a syndrome which has a broad range of etiologic factors depending on different clinical settings. Because AKI has significant impacts on prognosis in any clinical settings, early detection and intervention are necessary to improve the outcomes of AKI patients. This clinical guideline for AKI was developed by a multidisciplinary approach with nephrology, intensive care medicine, blood purification, and pediatrics. Of note, clinical practice for AKI management which was widely performed in Japan was also evaluated with comprehensive literature search