Bosnian Journal of Basic Medical Sciences (BJBMS)
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Stomach-specific c-Myc overexpression drives gastric adenoma in mice through AKT/mammalian target of rapamycin signaling
Get PDFGastric cancer (GC) is one of the most common malignant cancers in the world. c-Myc, a well-known oncogene, is commonly amplified in many cancers, including gastric cancer. However, it is still not completely understood how c-Myc functions in GC. Here, we generated a stomach-specific c-Myc transgenic mouse model to investigate its role in GC. We found that overexpression of c-Myc in Atp4b+ gastric parietal cells could induce gastric adenoma in mice. Mechanistically, c-Myc promoted tumorigenesis via the AKT/mTOR pathway. Furthermore, AKT inhibitor (MK-2206) or mTOR inhibitor (Rapamycin) inhibited the proliferation of c-Myc overexpressing gastric cancer cell lines. Thus, our findings highlight that gastric tumorigenesis can be induced by c-Myc overexpression through activation of the AKT/mTOR pathway
Dysbiosis of gut microbiota in inflammatory bowel disease: Current therapies and potential for microbiota-modulating therapeutic approaches
Get PDFThere is a growing body of evidence reinforcing the unique connections between the host microbiome, health, and diseases. Due to the extreme importance of the symbiotic relationship between the intestinal microbiome and the host, it is not surprising that any alteration in the gut microbiota would result in various diseases, including inflammatory bowel disease (IBD), Crohn’s disease, (CD) and ulcerative colitis (UC). IBD is a chronic, relapsing-remitting condition that is associated with significant morbidity, mortality, compromised quality of life, and costly medical care. Dysbiosis is believed to exacerbate the progression of IBD. One of the currently used treatments for IBD are anti-tumor necrosis factor (TNF) drugs, representing a biologic therapy that is reported to have an impact on the gut microbiota composition. The efficacy of anti-TNF agents is hindered by the possibility of non-response, which occurs in 10-20% of treated patients, and secondary loss of response, which occurs in up to 30% of treated patients. This underscores the need for novel therapies and studies that evaluate the role of the gut microbiota in these conditions. The success of any therapeutic strategy for IBD depends on our understanding of the interactions that occur between the gut microbiota and the host. In this review, the health and disease IBD-associated microbiota patterns will be discussed, in addition to the effect of currently used therapies for IBD on the gut microbiota composition, as well as new therapeutic approaches that can be used to overcome the current treatment constraints
Alectinib and lorlatinib function by modulating EMT-related proteins and MMPs in NSCLC metastasis
Get PDFMost advanced non-small cell lung cancer (NSCLC) patients are accompanied by brain metastasis which is the major cause of increased mortality. The fusion rearrangement of anaplastic lymphoma kinase (ALK) gene is an important feature of brain metastasis in lung cancer. The novel ALK inhibitors alectinib and lorlatinib are shown to be effective against NSCLC brain metastasis, while their underlying mechanism of action is unclear. Epithelial–mesenchymal transition (EMT) proteins and matrix metalloproteinases (MMPs) play important roles in brain metastasis by regulating the blood-brain barrier (BBB). To reveal the molecular function of alectinib and lorlatinib, we explored their effects on the cellular levels of EMT markers: VIM and FN1 and the matrix metalloproteinases MMP-9 and MMP-7. The mRNA and protein levels of VIM, FN1, MMP-9, and MMP-7 were elevated in H3122 cells. However, upon alectinib and lorlatinib treatment, the levels were significantly reduced. Similar results were obtained when these experiments were performed either in a dose-dependent or time-dependent manner. Furthermore, alectinib and lorlatinib also inhibited the cell viability and migration of H3122 cells. Interestingly, in comparison to individual drugs, the combination of alectinib and lorlatinib was found to be substantially more effective. Overall, these results suggest that alectinib and lorlatinib possibly function through the downregulation of MMPs and EMT in NSCLC metastasis
Raloxifene inhibits the overexpression of TGF-β1 in cartilage and regulates the metabolism of subchondral bone in rats with osteoporotic osteoarthritis
Get PDFOverexpression of transforming growth factor-beta 1 (TGF-β1) and subchondral bone remodelling play key roles in osteoarthritis (OA). Raloxifene (RAL) reduces the serum level of TGF-β1 in postmenopausal women. However, the effect of RAL on TGF-β1 expression in articular cartilage is still unclear. Therefore, we aimed to investigate the protective effect of RAL on osteoporotic osteoarthritis via affecting TGF-β1 expression in cartilage and the metabolism of subchondral bone. Osteoporotic osteoarthritis was induced by a combination of anterior cruciate transection (ACLT) and ovariectomy (OVX). Rats were divided into five groups (n = 12): The sham group, the ACLT group, the OVX group, the ACLT + OVX group, and the RAL group (ACLT + OVX + RAL, 6.25 mg/kg/day for 12 weeks). Assessment was performed by histomorphology, microcomputed tomography (micro-CT) scan, immunohistochemistry, and tartrate-resistant acid phosphatase (TRAP) staining. We found that severe cartilage degeneration was shown in the ACLT + OVX group. The histomorphological scores, the levels of TGF-β1, and its related catabolic enzymes and osteoclasts numbers in the ACLT + OVX group were higher than those in other groups (p < 0.05). Furthermore, structure model index (SMI) and trabecular spacing (Tb.Sp) were decreased (p < 0.05), while bone mineral density (BMD), bone volume fraction (BV/TV), and trabecular number (Tb.N) were increased by RAL compared with the ACLT + OVX group (p < 0.05). Our findings demonstrated that RAL in clinical doses retards the development of osteoporotic osteoarthritis by inhibiting the overexpression of TGF-β1 in cartilage and regulating the metabolism of subchondral bone. These results provide support for RAL in the expansion of clinical indication for prevention and treatment in postmenopausal osteoarthritis
Machine learning as the new approach in understanding biomarkers of suicidal behavior
No full textIn psychiatry, compared to other medical fields, the identification of biological markers that would complement current clinical interview, and enable more objective and faster clinical diagnosis, implement accurate monitoring of treatment response and remission, is grave. Current technological development enables analyses of various biological marks in high throughput scale at reasonable costs, and therefore ‘omic’ studies are entering the psychiatry research. However, big data demands a whole new plethora of skills in data processing, before clinically useful information can be extracted. So far the classical approach to data analysis did not really contribute to identification of biomarkers in psychiatry, but the extensive amounts of data might get to a higher level, if artificial intelligence in the shape of machine learning algorithms would be applied. Not many studies on machine learning in psychiatry have been published, but we can already see from that handful of studies that the potential to build a screening portfolio of biomarkers for different psychopathologies, including suicide, exists
Can NLR, PLR and LMR be used as prognostic indicators in patients with pulmonary embolism? A commentary
Get PDFWe read with great interest the article “Prognostic role of NLR, PLR, and LMR in patients with pulmonary embolism” by Köse et al.[1]. They found that the neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and lymphocyte-monocyte ratio (LMR) were related to the prognosis and clinical severity of patients with pulmonary embolism (PE). First of all, we congratulate the authors for their invaluable contribution to literature. However, we think that some points should be discussed regarding the use of these laboratory parameters.
White blood cell subtypes NLR, PLR, and LMR, have been associated with many inflammatory diseases, including PE [2,3]. These parameters, which can be easily determined by simple and easy measurement of systemic inflammation, maintain their importance today. However, these parameters are affected by many factors such as trauma, local or systemic infection, acute coronary syndromes, and malignancy [3-5]. For these reasons, it would be better for the authors to mention these factors and exclude them from the tables that included malignancy and trauma patients in the study.
It is known that drugs, including steroids, can increase neutrophils and decrease lymphocytes and therefore affect NLR, PLR, and LMR values [6]. Consequently, it will be more valuable to exclude patients who use drugs that may affect laboratory parameters. Besides, plasma inflammatory biomarkers are time-dependent variables. The time of sample collection and the time from the onset of the symptom to the sampling may impact the parameters [3-6]. Therefore, it is essential to identify the time from the first symptom to sample collection and the factors that may affect it. In conclusion, because NLR, PLR, and LMR can be affected by many factors, prospective studies with large populations are needed to show the accuracy of use in critically ill patients
Trends of incidence and prognosis of upper tract urothelial carcinoma
Get PDFThe purpose of this study was to investigate trends in the incidence of upper tract urothelial carcinoma (UTUC) in patients and to establish a reliable and practical nomogram based on significant clinical factors to predict the overall survival (OS) and cancer-specific survival (CSS) of UTUC patients. The Surveillance, Epidemiology, and End Results (SEER) database was used to extract data on UTUC patients between 1988 and 2015. Incidence was calculated using Joinpoint regression software, and trends were quantified by annual percentage change (APC). A nomogram was constructed using R software to predict the OS and CSS probabilities for individual patients. From 1988 to 2015, the incidence of UTUC showed a downward trend (1988: 1.57/100,000 to 2015: 1.51/100,000; APC=-0.1). After stratification according to sex, age and primary site, we found that the incidences of UTUC in males, patients 70+ years old and the renal pelvis were higher than those in females, patients <70 years old and ureter cancer patients. In the training cohort, the nomogram established based on multivariate Cox regression results showed better OS and CSS accuracy (OS: C-index=0.701, AUC=0.736; CSS: C-index=0.729, and AUC=0.688) than SEER stage. In addition, the calibration curves showed good consistency between the predicted and actual 3-, 5- and 10-year OS and CSS rates of the nomogram. In the past 30 years, the incidence of UTUC has shown a general downward trend, and the prognostic nomogram we established can provide a personalized risk assessment for the survival of UTUC patients. 
Surgical anatomy of microsurgical 3-level anterior cervical discectomy and fusion C4–C7
Get PDFAnterior cervical discectomy and fusion (ACDF) is one of the most common spinal procedures, frequently used for the treatment of cervical spine degenerative diseases. It was first described in 1958. Interestingly, to our knowledge, 3-level ACDF has not been previously published as a peer-reviewed video case with a detailed description of intraoperative microsurgical anatomy. In this video, we present the case of a 33-year-old male who presented with a combination of myelopathy (hyperreflexia and long tract signs in the upper and lower extremities) and bilateral radiculopathy of the upper extremities. He had been previously treated conservatively with physical therapy and pain management for 6 months without success. We performed 3-level microsurgical ACDF from C4 to C7. All 3 levels were decompressed, and bone allografts were placed to achieve intervertebral body fusion. A titanium plate was utilized from C4 to C7 for internal fixation. The patient was discharged home on the first postoperative day. His pain, numbness and tingling resolved, as well as his myelopathy. No perioperative complications were encountered. Herein we present the surgical anatomy of our operative technique including ertain technical tips. Written consent was obtained directly from the patient.
VIDEOhttps://vimeo.com/user128225853
VIDEO ANNOTATIONS01:13 — opening the surgery site02:29 — positioning of retractors03:02 — start of 3-level discectomy06:04 — allograft placement and fixation08:20 — drain placement and closur
The association between serine hydroxymethyl transferase 1 gene hypermethylation and ischemic stroke
Get PDFThis study aimed to determine the correlation between serine hydroxymethyl transferase 1 (SHMT1) gene methylation and ischemic stroke. A total of 202 age- and sex-matched individuals were included. Quantitative methylation-specific polymerase chain reaction (qMSP-PCR) was used to analyze the DNA methylation level. The plasma homocysteine (Hcy) concentration was much higher in ischemic cases than in controls (p = 0.009), while the high-density lipoprotein (HDL) levels in stroke cases were considerably lower than in controls (p = 0.005). A significantly higher level of SHMT1 methylation was observed in the ischemic strokes (58.82 ± 17.83%) compared to that in the controls (42.59 ± 20.76%, p < 0.001). The SHMT1 methylation level was strongly correlated with HDL concentration in the healthy controls (r = 0.517, p < 0.001), while the high plasma level of Hcy showed strong association with SHMT1 methylation in ischemic strokes (r = 0.346, p < 0.001). Receiver operating characteristic (ROC) analysis of curve indicated that SHMT1 methylation has been an acceptable indicator for ischemic stroke in female patients [all sexes, area under the curve (AUC) = 0.71, p < 0.001; male patients AUC = 0.62, p = 0.032; and female patients AUC = 0.79, p < 0.001] and in all ages (AUC = 0.71, p < 0.001). In our samples, DNA methylation levels of the STHMI gene were significantly correlated with ischemic stroke in Han Chinese. STHMI hypermethylation was significantly associated with the high Hcy concentration in ischemic stroke and had value as a potential indicator for female ischemic stroke
Respiratory depression in the post-anesthesia care unit: Mayo Clinic experience
Get PDFThe anesthesia recovery is a complex physiologic process as systems recover from the effects of surgery and anesthesia. Inadequate recovery of respiratory physiology can lead to severe hypoxemia-induced end-organ damage and even death. Emerging evidence suggests that signs of respiratory depression during early anesthesia recovery may portend increased risk for future severe adverse events. This article briefly reviews the Mayo Clinic research experience and advances in clinical practice. From the implementation of a step-down model of discharge criteria in the post-anesthesia care unit (PACU), consisting of PACU nurses monitoring patients in predetermined periods for signs of respiratory depression, and delaying PACU discharge for patients who exhibit signs of respiratory depression, and early intervention in high-risk patients. Subsequent studies found that even a single episode of respiratory depression in the PACU was strongly associated with subsequent respiratory complications. Further, patient baseline characteristics found to be associated with respiratory depression included obstructive sleep apnea and low body weight, and surgical factors associated with increased risk included the use of preoperative sustained-release opioids, perioperative gabapentinoid use, higher intraoperative opioids, isoflurane as the volatile anesthetic, and longer surgical duration. Based in part of Mayo Clinic research, the FDA issued a warning in 2019 on gabapentinoids use and respiratory complications, increasing the recommended level of respiratory vigilance in patients using this medication. Understanding the complex nature of postoperative respiratory events requires a range of translational and clinical research and constant update of practice