Notes

Long-Term Outcomes of Sglt2 Deletion in Bone tissue as well as Mineral Fat burning capacity in Rats.
Inflammatory molecules and exosomes are crucial for signal transduction between tumor-associated macrophages and tumor cells. IL-6, a key inflammatory molecule secreted by M2 macrophages after polarization, can mediate malignant progression of pancreatic cancer (PC). However, the functions and mechanisms of IL-6 and tumor-derived exosomes in tumor-associated macrophages and PC remain unclear. Transcriptome chip and quantitative reverse transcription PCR experiments indicated that FGD5-AS1 induced IL-6 and high FGD5-AS1 expression correlated with the poor prognosis in PC patients. RNA pulldown, mass spectrometry, and dual luciferase reporter assays were used to identify the mechanism of exosomal FGD5-AS1 in promoting PC progression and M2 macrophage polarization. FGD5-AS1 exerted cancer-promoting functions when co-cultured with M2 macrophages. PC-derived exosomal FGD5-AS1 stimulated M2 macrophage polarization by activating STAT3/NF-κB pathway. FGD5-AS1 interacts with p300, resulting in STAT3 acetylation, thus promoting nuclear localization and transcriptional activity of STAT3/NF-κB. AZ 960 These data indicated that PC cells generate FGD5-AS1-rich exosomes, which cause M2 macrophage polarization to promote the malignant behaviors of PC cells. Targeting exosomal FGD5-AS1 may provide a potential diagnosis and treatment strategy for PC.Prostate cancer is frequently characterized as a multifocal disease with great intratumoral heterogeneity as well as a high propensity to metastasize to bone. Consequently, modeling prostate tumor has remained a challenging task for researchers in this field. In the past decades, genomic advances have led to the identification of key molecular alterations in prostate cancer. Moreover, resistance towards second-generation androgen-deprivation therapy, namely abiraterone and enzalutamide has unveiled androgen receptor-independent diseases with distinctive histopathological and clinical features. In this review, we have critically evaluated the commonly used preclinical models of prostate cancer with respect to their capability of recapitulating the key genomic alterations, histopathological features and bone metastatic potential of human prostate tumors. In addition, we have also discussed the potential use of the emerging organoid models in prostate cancer research, which possess clear advantages over the commonly used preclinical tumor models. We anticipate that no single model can faithfully recapitulate the complexity of prostate cancer, and thus, propose the use of a cost- and time-efficient integrated tumor modeling approach for future prostate cancer investigations.TGFβ contributes to chemoresistance in advanced colorectal cancer (CRC) via diverse immune-microenvironment mechanisms. Here, we found that cancer cell autonomous TGFβ directly triggered tumor programmed cell death 1 ligand 1 (PD-L1) upregulation, resulting in resistance to chemotherapy. Inhibition of tumor PD-L1 expression sensitized cancer cells to chemotherapy, reduced lung metastasis and increased the influx of CD8+ T cells. However, chemorefractory cancer cell-derived CSF1 recruited TAMs for TGFβ-mediated PD-L1 upregulation via a vicious cycle. High infiltration of macrophages was clinically correlated with the status of tumor PD-L1 after chemotherapy treatment in CRC patients. We found that depletion of immunosuppressive CSF1R+ TAM infiltration and blockade of the TGFβ receptor resulted in an increased influx of cytotoxic CD8+ T and effector memory CD8+ cells, a reduction in regulatory T cells, and a synergistic inhibition of tumor growth when combined with chemotherapy. These findings show that CSF1R+ TAMs and TGFβ are the dominant components that regulate PD-L1 expression within the immunosuppressive tumor microenvironment, providing a therapeutic strategy for advanced CRC patients.
A total of 74 570 potentially naturally inducible chromosomal AmpC-producing (PNIC-AmpC) Enterobacterales isolates included in the Antimicrobial Testing Leadership and Surveillance Programme were obtained worldwide during 2012-2019 (22 503 from 2012-2014 and 52 067 from 2015-2019). Of these isolates, 117 and 711 obtained during 2012-2014 and 2015-2019, respectively, were carbapenem-resistant Enterobacterales (PNIC-AmpC-CRE). The MICs of ceftazidime-avibactam for these isolates were determined using the broth microdilution method.

Genes encoding different Ambler classes of β-lactamases were investigated using multiplex PCR. After 97 isolates harbouring genes encoding metallo-β-lactamases (MβL) were excluded, 731 PNIC-AmpC MβL-negative CRE isolates (101 from 2012-2014 and 630 from 2015-2019) were included in this study.

Enterobacter cloacae (E. cloacae) complex species, Escherichia coli (E. coli) and Citrobacter freundii (C. freundii) complex species accounted for 36.3% (n=265), 30.4% (n=222) and 11.8% (n=86), respectively, followed by Providencia species (n=72), Serratia species (n=52) and Klebsiella aerogenes (n=34). The resistance rates to ceftazidime-avibactam for the overall PNIC-AmpC MβL-negative CRE isolates markedly differed between the two periods (35.6% vs. 63.3%; P < 0.001). Similar trends were observed for the MβL-negative-CR-E. cloacae complex species (47.4% vs. 65.2%; P=0.046) and MβL-negative-CR-E. coli (16.2% vs. 63.8%; P < 0.001) but not for MβL-negative-CR-C. freundii complex species (40% vs. 62%; P=0.153). Amongst the PNIC-AmpC MβL-negative CRE isolates, resistance rates to ceftazidime-avibactam worsened.

Caution should be taken when empirically prescribing ceftazidime-avibactam for infections caused by PNIC-AmpC-CRE before susceptibility data are available.
Caution should be taken when empirically prescribing ceftazidime-avibactam for infections caused by PNIC-AmpC-CRE before susceptibility data are available.Carbapenems, tigecycline and colistin are three important antimicrobial agents for the treatment of clinical infections caused by multidrug-resistant Enterobacteriaceae. Here we characterised the formation of hybrid plasmids containing mcr-8 and blaNDM-1 or tmexCD1-toprJ1 that could confer resistance to colistin and carbapenems or tigecycline. More specifically, these clinically important genes could be co-transferred through IS26- and ltrA-mediated plasmid fusion to clinical isolates during conjugation under single drug (colistin) selection, following which the recipient strains became carbapenem- or tigecycline-resistant. The transferability and stability of these hybrid multidrug resistance (MDR) plasmids depend on the bacterial host and the presence of antibiotics. Further evolution and adaptation of these hybrid plasmids may facilitate their emergence and spread, which is of great concern for clinical therapy.Mesial temporal lobe epilepsy (MTLE) is the most common type of focal refractory epilepsy and is characterized by recurring seizures that are often refractory to medication. Since parvalbumin-positive (PV) interneurons were recently shown to play significant roles in ictogenesis, we established here how bilateral optogenetic stimulation of these interneurons in the hippocampus CA3 regions modulates seizures, interictal spikes and high-frequency oscillations (HFOs; ripples 80-200 Hz, fast ripples 250-500 Hz) in the pilocarpine model of MTLE. Bilateral optogenetic stimulation of CA3 PV-positive interneurons at 8 Hz (lasting 30 s, every 2 min) was implemented in PV-ChR2 mice for 8 consecutive days starting on day 7 (n = 8) or on day 13 (n = 6) after pilocarpine-induced status epilepticus (SE). Seizure occurrence was higher in both day 7 and day 13 groups of PV-ChR2 mice during periods of optogenetic stimulation ("ON"), compared to when stimulation was not performed ("OFF") (day 7 group = p less then 0.01, day 13 group = p less then 0.01). In the PV-ChR2 day 13 group, rates of seizures (p less then 0.05), of interictal spikes associated with fast ripples (p less then 0.01), and of isolated fast ripples (p less then 0.01) during optogenetic stimulations were significantly higher than in the PV-ChR2 day 7 group. Our findings reveal that bilateral activation of PV-interneurons in the hippocampus (leading to a presumptive increase in GABA signaling) favors ictogenesis. These effects may also mirror the neuropathological changes that occur over time after SE in this animal model.
Pneumococcal pneumonia has a high morbidity and mortality in adults, especially those ≥65 years old. In the past decade, pneumococcal vaccination programs have been initiated worldwide, however, few data concerning mortality changes are available in pneumococcal pneumonia patients and there are no reports clarifying these current changes in Japan.

Japanese patients ≥65 years old hospitalized with pneumococcal pneumonia between April 2012 and March 2018 were analyzed using the Diagnostic Procedure Combination database. In-hospital mortality was evaluated, and the odds ratios for this outcome in each fiscal year compared with that in 2012 was analyzed using multivariable logistic regression models.

Between 2012 and 2017, data of 47,375 pneumococcal pneumonia patients ≥65 years old were extracted. The incidence per 1000 person-years for in-hospital mortality was 60.4 in 2012, 56.8 in 2013, 63.2 in 2014, 56.1 in 2015, 73.0 in 2016, and 67.4 in 2017 and the odds ratios for in-hospital mortality in 2013, 2014, 2015, 2016, and 2017 compared with that in 2012 were 1.00, 1.05, 1.04, 1.06, and 0.98, respectively. There were no significant differences between 2012 and each year from 2013 to 2017. Low BMI; low ADL score; high A-DROP score; comorbid malignancy and heart failure; the coexistence of invasive pneumococcal infection; and the use of invasive mechanical ventilation were independent risk factors for in-hospital mortality.

There were no changes in in-hospital mortality in pneumococcal pneumonia patients between 2012 or each year from 2013 to 2017 and further epidemiological observations are necessary.
There were no changes in in-hospital mortality in pneumococcal pneumonia patients between 2012 or each year from 2013 to 2017 and further epidemiological observations are necessary.
The Japanese Respiratory Society (JRS) scoring system is a useful tool for the rapid presumptive diagnosis of atypical pneumonia in non-elderly (aged <60 years) patients. As SARS-CoV-2 vaccination progresses, COVID-19 in elderly people has markedly reduced. We investigated changes in diagnostic usefulness of the JRS scoring system in COVID-19 pneumonia between the Delta variant group (vaccination period) and non-Delta variant group (before the vaccination period).

This study was conducted at five institutions and assessed a total of 1121 patients with COVID-19 pneumonia (298 had the Delta variant). During the vaccination period, the Delta variant has spread and replaced the Alfa variant. We evaluated the vaccination period as the Delta variant group.

Among the six parameters of the JRS scoring system, matching rates of two parameters were higher in the Delta variant group than the non-Delta variant group (pre-vaccination period) age <60 years (77.5% vs 42.2%, P<0.0001) and no or minor comorbid illness (69.1% vs 57.8%, p=0.0007). The sensitivity of the diagnosis of atypical pneumonia in patients with COVID-19 pneumonia was significantly higher in the Delta variant group compared with the non-Delta variant group (80.2% vs 58.3%, p<0.0001). When the diagnostic sensitivity was analyzed for different ages, the diagnostic sensitivities for the Delta variant and non-Delta variant groups were 92.6% and 95.5% for non-elderly patients and 39.1% and 32.5% for elderly patients, respectively.

Our results demonstrated that the JRS scoring system is a useful tool for distinguishing between COVID-19 pneumonia and bacterial pneumonia in the COVID-19 vaccination period, but not before the vaccination period.
Our results demonstrated that the JRS scoring system is a useful tool for distinguishing between COVID-19 pneumonia and bacterial pneumonia in the COVID-19 vaccination period, but not before the vaccination period.
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