Comparison of the relative efficacy of ß-lactam/ß-lactamase inhibitors and carbapenems in the treatment of complicated urinary tract infections caused by ceftriaxone-non-susceptible Enterobacterales: a multicentre retrospective observational cohort study.

BACKGROUND: Treating complicated urinary tract infections (cUTIs) caused by ESBL-producing Enterobacterales represents a significant clinical challenge. The present study was thus developed to explore the relative efficacy of ß-lactam/ß-lactamase inhibitors (BLBLIs) and carbapenems for the treatment of hospitalized patients suffering from cUTIs caused by BLBLI-susceptible ceftriaxone-non-susceptible Enterobacterales. METHODS: Data from 557 patients from four Chinese teaching hospitals diagnosed with cUTIs caused by ceftriaxone-non-susceptible Enterobacterales from January 2017 to May 2022 were retrospectively assessed. RESULT: The 30 day rate of treatment failure, defined by unresolved symptoms or mortality, was 10.4% (58/557). Independent predictors of 30 day treatment failure included immunocompromised status, bacteraemia, septic shock, lack of infection source control and appropriate empirical treatment. When data were controlled for potential confounding variables, BLBLI treatment exhibited a comparable risk of 14 day (OR 1.61, 95% CI 0.86-3.00, P = 0.133) and 30 day treatment failure (OR 1.45, 95% CI 0.66-3.15, P = 0.354) relative to carbapenem treatment for the overall cohort of patients. In contrast, BLBLI treatment in immunocompromised patients was associated with an elevated risk of both 14 day (OR 3.18, 95% CI 1.43-7.10, P = 0.005) and 30 day treatment failure (OR 3.06, 95% CI 1.07-8.80, P = 0.038) relative to carbapenem treatment. CONCLUSIONS: These results suggested that carbapenem treatment may be superior to BLBLI treatment for immunocompromised patients suffering from cUTIs caused by ceftriaxone-non-susceptible Enterobacterales species. However, these results will need to be validated in appropriately constructed randomized controlled trials to ensure appropriate patient treatment.

Application of endoscopic ultrasonography for detecting esophageal lesions based on convolutional neural network.

BACKGROUND: A convolutional neural network (CNN) is a deep learning algorithm based on the principle of human brain visual cortex processing and image recognition. AIM: To automatically identify the invasion depth and origin of esophageal lesions based on a CNN. METHODS: A total of 1670 white-light images were used to train and validate the CNN system. The method proposed in this paper included the following two parts: (1) Location module, an object detection network, locating the classified main image feature regions of the image for subsequent classification tasks; and (2) Classification module, a traditional classification CNN, classifying the images cut out by the object detection network. RESULTS: The CNN system proposed in this study achieved an overall accuracy of 82.49%, sensitivity of 80.23%, and specificity of 90.56%. In this study, after follow-up pathology, 726 patients were compared for endoscopic pathology. The misdiagnosis rate of endoscopic diagnosis in the lesion invasion range was approximately 9.5%; 41 patients showed no lesion invasion to the muscularis propria, but 36 of them pathologically showed invasion to the superficial muscularis propria. The patients with invasion of the tunica adventitia were all treated by surgery with an accuracy rate of 100%. For the examination of submucosal lesions, the accuracy of endoscopic ultrasonography (EUS) was approximately 99.3%. Results of this study showed that EUS had a high accuracy rate for the origin of submucosal lesions, whereas the misdiagnosis rate was slightly high in the evaluation of the invasion scope of lesions. Misdiagnosis could be due to different operating and diagnostic levels of endoscopists, unclear ultrasound probes, and unclear lesions. CONCLUSION: This study is the first to recognize esophageal EUS images through deep learning, which can automatically identify the invasion depth and lesion origin of submucosal tumors and classify such tumors, thereby achieving good accuracy. In future studies, this method can provide guidance and help to clinical endoscopists.

Acetyl-11-keto-ß-boswellic acid inhibits proliferation and induces apoptosis of gastric cancer cells through the phosphatase and tensin homolog /Akt/ cyclooxygenase-2 signaling pathway.

BACKGROUND: Gastric cancer is one of the most common malignant tumors of the digestive system worldwide, posing a serious danger to human health. Cyclooxygenase (COX)-2 plays an important role in the carcinogenesis and progression of gastric cancer. Acetyl-11-keto-ß-boswellic acid (AKBA) is a promising drug for cancer therapy, but its effects and mechanism of action on human gastric cancer remain unclear. AIM: To evaluate whether the phosphatase and tensin homolog (PTEN)/Akt/COX-2 signaling pathway is involved in the anti-tumor effect of AKBA in gastric cancer. METHODS: Human poorly differentiated BGC823 and moderately differentiated SGC7901 gastric cancer cells were routinely cultured in Roswell Park Memorial Institute 1640 medium supplemented with 10% fetal bovine serum and 1% penicillin/streptomycin. Gastric cancer cell proliferation was determined by methyl thiazolyl tetrazolium colorimetric assay. Apoptosis was measured by flow cytometry. Cell migration was assessed using the wound-healing assay. Expression of Bcl-2, Bax, proliferating cell nuclear antigen, PTEN, p-Akt, and COX-2 were detected by Western blot analysis. A xenograft nude mouse model of human gastric cancer was established to evaluate the anti-cancer effect of AKBA in vivo. RESULTS: AKBA significantly inhibited the proliferation of gastric cancer cells in a dose- and time-dependent manner, inhibited migration in a time-dependent manner, and induced apoptosis in a dose-dependent manner in vitro; it also inhibited tumor growth in vivo. AKBA up-regulated the expression of PTEN and Bax, and down-regulated the expression of proliferating cell nuclear antigen, Bcl-2, p-Akt, and COX-2 in a dose-dependent manner. The PTEN inhibitor bpv (Hopic) reversed the high expression of PTEN and low expression of p-Akt and COX-2 that were induced by AKBA. The Akt inhibitor MK2206 combined with AKBA down- regulated the expression of p-Akt and COX-2, and the combined effect was better than that of AKBA alone. CONCLUSION: AKBA inhibits the proliferation and migration and promotes the apoptosis of gastric cancer cells through the PTEN/Akt/COX-2 signaling pathway.

A Single-Shot Region-Adaptive Network for Myotendinous Junction Segmentation in Muscular Ultrasound Images.

Tracking the myotendinous junction (MTJ) in consecutive ultrasound images is crucial for understanding the mechanics and pathological conditions of the muscle-tendon unit. However, the lack of reliable and efficient identification of MTJ due to poor image quality and boundary ambiguity restricts its application in motion analysis. In recent years, with the rapid development of deep learning, the region-based convolution neural network (RCNN) has shown great potential in the field of simultaneous objection detection and instance segmentation in medical images. This article proposes a region-adaptive network (RAN) to localize MTJ region and to segment it in a single shot. Our model learns about the salient information of MTJ with the help of a composite architecture. Herein, a region-based multitask learning network explores the region containing MTJ, while a parallel end-to-end U-shaped path extracts the MTJ structure from the adaptively selected region for combating data imbalance and boundary ambiguity. By demonstrating the ultrasound images of the gastrocnemius, we showed that the RAN achieves superior segmentation performance when compared with the state-of-the-art Mask RCNN method with an average Dice score of 80.1%. Our proposed method is robust and reliable for advanced muscle and tendon function examinations obtained by ultrasound imaging.

Pre-clinical characterization of PKC412, a multi-kinase inhibitor, against colorectal cancer cells.

The potential effect of PKC412, a small molecular multi-kinase inhibitor, in colorectal cancer (CRC) cells was evaluated here. We showed that PKC412 was cytotoxic and anti-proliferative against CRC cell lines (HT-29, HCT-116, HT-15 and DLD-1) and primary CRC cells. PKC412 provoked caspase-dependent apoptotic death, and induced G2-M arrest in the CRC cells. AKT activation was inhibited by PKC412 in CRC cells. Reversely, expression of constitutively-active AKT1 (CA-AKT1) decreased the PKC412's cytotoxicity against HT-29 cells. We propose that Bcl-2 could be a primary resistance factor of PKC412. ABT-737, a Bcl-2 inhibitor, or Bcl-2 siRNA knockdown, dramatically potentiated PKC412's lethality against CRC cells. Forced Bcl-2 over-expression, on the other hand, attenuated PKC412's cytotoxicity. Significantly, PKC412 oral administration suppressed AKT activation and inhibited HT-29 tumor growth in nude mice. Mice survival was also improved with PKC412 administration. These results indicate that PKC412 may have potential value for CRC treatment.

Gastrin acting on the cholecystokinin2 receptor induces cyclooxygenase-2 expression through JAK2/STAT3/PI3K/Akt pathway in human gastric cancer cells.

Gastrin, cholecystokinin2 receptor (CCK2R), and cyclooxygenase-2 (COX-2) have been implicated in the carcinogenesis and progression of gastric cancer. Our study demonstrated that antagonist or siRNA against CCK2R blocked amidated gastrin (G17)-induced activation of STAT3 and Akt in gastric cancer cell lines. G17-increased COX-2 expression and cell proliferation were effectively blocked by CCK2R antagonist and inhibitors of JAK2 and PI3K. In addition, knockdown of STAT3 expression significantly attenuated G17-induced PI3K/Akt activation, COX-2 expression, and cell proliferation. These results suggest that CCK2R-mediated COX-2 up-regulation via JAK2/STAT3/PI3K/Akt pathway is involved in the proliferative effect of G17 on human gastric cancer cells.

Downregulation of miR-101 in gastric cancer correlates with cyclooxygenase-2 overexpression and tumor growth.

Cyclooxygenase-2 (COX-2) plays an important role in the carcinogenesis and progression of gastric cancer. It has been demonstrated that COX-2 overexpression depends on different cellular pathways, involving both transcriptional and post-transcriptional regulation. MicroRNAs (miRNAs) are small, noncoding RNAs that function as post-transcriptional regulators. Here, we characterize miR-101 expression and its role in the regulation of COX-2 expression, which in turn, will provide us with additional insights into the potential therapeutic benefits of exogenous miR-101 for treatment of gastric cancer. Our results showed that miR-101 levels in gastric cancer tissues were significantly lower than those in the matched normal tissue (P < 0.01). Furthermore, lower levels of miR-101 were associated with increased tumor invasion and lymph node metastasis (P < 0.05). We also found an inverse correlation between miR-101 and COX-2 expression in both gastric cancer specimens and cell lines. Significant decreases in COX-2 mRNA and COX-2 levels were observed in the pre-miR-101-infected gastric cancer cells. One possible mechanism of interaction is that miR-101 inhibited COX-2 expression by directly binding to the 3'-UTR of COX-2 mRNA. Overexpression of miR-101 in gastric cancer cell lines also inhibited cell proliferation and induced apoptosis in vitro, as well as inhibiting tumor growth in vivo. These results collectively indicate that miR-101 may function as a tumor suppressor in gastric cancer, with COX-2 as a direct target.