miR-192 Is Overexpressed and Promotes Cell Proliferation in Prostate Cancer.

OBJECTIVE: Prostate cancer (PCa) is one of the most prevalent types of cancer among men worldwide. The incidence of PCa is increasing in China. Therefore, there is an urgent need to identify novel diagnostic and prognostic markers for PCa to improve the treatment of the disease. METHODS: The Cancer Genome Atlas (TCGA) and GEO database were used to analyze the expression of miR-192, and the relationship between miR-192 and the clinical features of patients with PCa. Cell cycle and cell proliferation assay were used to detect the functional roles of miR-192 in PCa. Bioinformatic analysis for miR-192-5p was performed using gene ontology and KEGG analysis. RESULTS: By analyzing the dataset of TCGA, we found that miR-192 was overexpressed in PCa samples compared to normal tissues and was upregulated in high-grade PCa compared to low-grade PCa. We also observed that higher miR-192 expression was associated with a shorter biochemical recurrence-free survival time. Our results also demonstrated that miR-192 promoted PCa cell proliferation and cell cycle progression. CONCLUSION: These results suggest that miR-192 may be considered for use as a potential diagnostic and therapeutic target of PCa.

A model for predicting the dose to the parotid glands based on their relative overlapping with planning target volumes during helical radiotherapy.

The sparing of the parotid glands in the treatment of head and neck cancers is of clinical relevance as high doses to the salivary glands may result in xerostomia. Xerostomia is a major cause of decreased quality of life for head and neck patients. This paper explores the relationship between the overlap of the target volumes and their expansions with the parotid glands for helical delivery plans and their ability to be spared. Various overlapping volumes were examined, and an overlap with a high statistical relevance was found. A model that predicts exceeding tolerance parotid mean dose based on its fractional overlapping volume with PTVs was developed. A fractional overlapping volume of 0.083 between the parotid gland and the high dose PTV plus 5 mm expansion - was determined to be the threshold value to predict parotid Dmean  > 26 Gy for parotids that overlap with the high dose PTV plus 5 mm expansion. If the parotid gland only overlaps with the intermediate dose target (and/or low dose target) and the overlapping volume of the parotid gland and the intermediate dose target is less than 25%, the parotid mean dose is likely less than 26 Gy. If the parotid overlaps with the low dose target only then the mean dose to the parotid is likely to be less than 26 Gy. This finding will prove as a very useful guide for the physicians and planners involved in the planning process to know prior whether the parotid glands will be able to be spared with the current set of target volumes or if revisions are necessary. This work will serve as a helpful guide in the planning process of head and neck target cases.

Epidermal Growth Factor-Containing Fibulin-Like Extracellular Matrix Protein 1 (EFEMP1) Acts as a Potential Diagnostic Biomarker for Prostate Cancer.

BACKGROUND The aim of this study was to detect the expression of epidermal growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1) and estimate its diagnostic value in prostate cancer (PCa). MATERIAL AND METHODS EFEMP1 expression in serum and urine of patients with PCa, benign controls and healthy controls at mRNA and protein level were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) analysis, respectively. The chi-square test was used to analyze the relationship between EFEMP1 expression and clinical factors of patients with PCa. A receiver operating characteristic (ROC) curve was established to evaluate the potential values of EFEMP1 for the diagnosis of PCa. RESULTS The relative expression of EFEMP1 was significantly decreased in patients with PCa compared with that in the benign controls and healthy individuals, both at mRNA and protein levels (P<0.05). In the postoperative serum, the EFEMP1 expression was significantly higher than that in preoperative serum at 2 levels. Urine EFEMP1 expression was also down-regulated in patients with PCa compared to that in the other 2 control groups. The low expression of EFEMP1 was obviously affected by Gleason's score, serum PSA, pathological stage, and lymph node metastasis. Moreover, there was a significant inverse correlation between EFEMP1 expression and PSA levels. The ROC curve revealed that EFEMP1 distinguished PCa patients from healthy controls, with a high AUC of 0.908, corresponding with high sensitivity and specificity, which was significantly higher than the PSA value. CONCLUSIONS Serum EFEMP1 is down-regulated and involved in the progression of PCa. It may serve as a useful diagnostic biomarker, with better diagnostic accuracy than PSA in PCa.

A Novel Immobilization Method for the Treatment of Head and Neck Cancer Using 3D Printing.

Proper immobilization is critical for the delivery of high-quality radiation therapy. In cases when traditional immobilization is not feasible, 3-dimensional (3D) printing may provide a better-tolerated custom immobilization that is comparably effective. We present the successful treatment of a patient with inoperable oropharyngeal squamous cell carcinoma who was unable to tolerate traditional immobilization. To avoid covering the face, we created a 3D-printed cradle for the back of his head and neck. This design enabled the patient to tolerate traditional simulation scans with and without intravenous contrast and was subsequently able to undergo volumetric modulated arc therapy treatment. He successfully underwent treatment without evidence of disease more than 2 years after completion. The effect of 3D printing within the context of radiation oncology, as well as in other specialties, will undoubtedly continue to increase the variety of treatment options available to patients.

ACAT1 suppresses clear cell renal cell carcinoma progression by AMPK mediated fatty acid metabolism.

Renal cell carcinoma (RCC) stands as a prevalent malignancy within urological pathology, exhibiting a noteworthy escalation in its incidence. Despite being a mitochondrial enzyme, the precise role of Acetyl-CoA Acetyltransferase 1 (ACAT1) in RCC remains elusive. In this investigation, we employed bioinformatics methodologies to assess the expression patterns and prognostic significance across various RCC subtypes, encompassing clear cell renal cell carcinoma (ccRCC), papillary cell carcinoma, and chromophobe cell carcinoma. Our findings unveil a close correlation between ACAT1 expression and the prognostic implications specifically within ccRCC. Through both in vitro and in vivo overexpression studies, we delineated the functional and mechanistic facets of ACAT1 in impeding the progression of ccRCC. Our results unequivocally demonstrated that ACAT1 overexpression markedly curtailed proliferation, invasion, and metastasis of ccRCC cells in both in vivo models and cell cultures. Mechanistically, ACAT1's inhibitory effect on the AMPK signaling pathway orchestrated a regulatory role in modulating fatty acid metabolism, thereby effectively restraining the advancement of ccRCC. Collectively, our findings underscore ACAT1 as a pivotal tumor suppressor, instrumental in curtailing the proliferation, migration, and invasion of ccRCC by governing fatty acid metabolism through the AMPK signaling pathway. These insights posit ACAT1 as a potential predictive biomarker and therapeutic target warranting further exploration in RCC management.

Targeting novel regulated cell death: Ferroptosis, pyroptosis and necroptosis in anti-PD-1/PD-L1 cancer immunotherapy.

Chemotherapy, radiotherapy, and immunotherapy represent key tumour treatment strategies. Notably, immune checkpoint inhibitors (ICIs), particularly anti-programmed cell death 1 (PD1) and anti-programmed cell death ligand 1 (PD-L1), have shown clinical efficacy in clinical tumour immunotherapy. However, the limited effectiveness of ICIs is evident due to many cancers exhibiting poor responses to this treatment. An emerging avenue involves triggering non-apoptotic regulated cell death (RCD), a significant mechanism driving cancer cell death in diverse cancer treatments. Recent research demonstrates that combining RCD inducers with ICIs significantly enhances their antitumor efficacy across various cancer types. The use of anti-PD-1/PD-L1 immunotherapy activates CD8+ T cells, prompting the initiation of novel RCD forms, such as ferroptosis, pyroptosis, and necroptosis. However, the functions and mechanisms of non-apoptotic RCD in anti-PD1/PD-L1 therapy remain insufficiently explored. This review summarises the emerging roles of ferroptosis, pyroptosis, and necroptosis in anti-PD1/PD-L1 immunotherapy. It emphasises the synergy between nanomaterials and PD-1/PD-L1 inhibitors to induce non-apoptotic RCD in different cancer types. Furthermore, targeting cell death signalling pathways in combination with anti-PD1/PD-L1 therapies holds promise as a prospective immunotherapy strategy for tumour treatment.

[Retracted] Silencing of RTKN2 by siRNA suppresses proliferation, and induces G1 arrest and apoptosis in human bladder cancer cells.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that certain of the Transwell migration assay data shown in Fig. 4D on p. 4876 were strikingly similar to data that had already been published in different form in another article written by different authors at a different research institute. In addition, a pair of the data panels in Fig. 4D were overlapping, indicating that data derived from the same original source had been used to represent what were intended to be the results obtained from differently performed experiments.  Owing to the fact that the contentious data in the above article had already been published prior to its submission to Molecular Medicine Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [Molecular Medicine Reports 13: 4872­4878, 2016; DOI: 10.3892/mmr.2016.5127].

Spatial memory requires hypocretins to elevate medial entorhinal gamma oscillations.

The hypocretin (Hcrt) (also known as orexin) neuropeptidic wakefulness-promoting system is implicated in the regulation of spatial memory, but its specific role and mechanisms remain poorly understood. In this study, we revealed the innervation of the medial entorhinal cortex (MEC) by Hcrt neurons in mice. Using the genetically encoded G-protein-coupled receptor activation-based Hcrt sensor, we observed a significant increase in Hcrt levels in the MEC during novel object-place exploration. We identified the function of Hcrt at presynaptic glutamatergic terminals, where it recruits fast-spiking parvalbumin-positive neurons and promotes gamma oscillations. Bidirectional manipulations of Hcrt neurons' projections from the lateral hypothalamus (LHHcrt) to MEC revealed the essential role of this pathway in regulating object-place memory encoding, but not recall, through the modulation of gamma oscillations. Our findings highlight the significance of the LHHcrt-MEC circuitry in supporting spatial memory and reveal a unique neural basis for the hypothalamic regulation of spatial memory.

Homeostatic Shrinkage of Dendritic Spines Requires Melatonin Type 3 Receptor Activation During Sleep.

High-frequency oscillatory activity in cognition-related neural circuits during wakefulness consistently induces the growth of dendritic spines and axonal terminals. Although these structural changes are essential for cognitive functions, it is hypothesized that if these newly expanded structures fail to establish functional connections, they may become superfluous. Sleep is believed to facilitate the reduction of such redundant structures to maintain neural homeostasis. However, the mechanisms underlying this pruning process during sleep remain poorly understood. In this study, that melatonin type 3 receptors (MT3Rs) are selectively expressed in the stellate neurons of the medial entorhinal cortex (MEC) is demonstrated, an area where high melatonin levels are detected during sleep. Activation of MT3Rs during sleep initiates the shrinkage of dendritic spines in stellate neurons by downregulating neural network activity and dephosphorylating synaptic proteins in the MEC. This process is disrupted when MT3R expression is knocked down or when MT3Rs are blocked during sleep. Notably, interference with MT3Rs in the MEC during sleep impairs the acquisition of spatial memory but does not affect object memory acquisition following sleep. These findings reveal novel molecular mechanisms involving melatonin and MT3Rs in the regulation of dendritic spine shrinkage during sleep, which is crucial for the acquisition and consolidation of spatial memory.

The relationship between serum albumin and prostate-specific antigen: A analysis of the National Health and Nutrition Examination Survey, 2003-2010.

Background: Previous studies have shown that serum albumin is associated with prostate cancer (PCa), but not with prostate-specific antigen (PSA) levels in populations without PCa history. Therefore, we analyzed secondary data provided by the National Health and Nutrition Examination Survey (NHANES) (2003-2010). Methods: In total, 5,469 participants were selected from the NHANES database (2003-2010). Serum albumin and PSA levels were serially considered independent and dependent variables, serially. A number of covariates were included in this study, including demographic, dietary, physical examination, and comorbidity data. Using weighted linear regression model and smooth curve fitting, the linear and non-linear relationship between serum albumin and PSA was investigated. Results: After modulating underlying interference factors, the weighted multivariate linear regression analysis revealed that serum albumin did not independently predict PSA levels (ß = -0.009 95%CI: -0.020, 0.002). Nevertheless, a non-linear relationship was found between serum albumin and PSA, with a point of 41 g/L. Left of the inflection point, the effect size, 95%CI, and P-value were 0.019 (log2 transformation) (-0.006, 0.043) and 0.1335, respectively. We found a negative association between serum albumin and PSA on the right side of the inflection point, with effect size, 95%CI, and a P-value of -0.022 (log2 transformation) (-0.037, -0.007), 0.0036. Conclusion: In summary, serum albumin and PSA levels are not linearly related. When serum albumin levels exceed 41 g, serum albumin levels are negatively associated with PSA levels.

Phase I, Randomized, Placebo-Controlled, Dose-Escalation Study of GB223, a Fully-Humanized Monoclonal Antibody to RANKL, in Healthy Chinese Adults.

BACKGROUND: GB223 is a novel, fully-humanized monoclonal antibody against the receptor activator of nuclear factor-kappa B ligand (RANKL). In this phase I study, the safety, tolerability, pharmacokinetics, pharmacodynamics, and immunogenicity of GB223 were investigated. PATIENTS AND METHODS: This was a randomized, double-blinded, placebo-controlled, single-dose escalation study conducted in 44 healthy Chinese adults. Participants were randomly assigned to receive a single subcutaneous injection dose of 7, 21, 63, 119, or 140 mg of GB223 (n = 34) or placebo (n = 10) and were followed up for 140-252 days. RESULTS: The results of noncompartmental analysis showed that GB223 was slowly absorbed after dosing, with a time to reach maximum concentration (Tmax) ranging from 5 to 11 days. Serum GB223 concentrations decreased slowly, with a long half-life ranging from 7.91 to 19.60 days. A two-compartment Michaelis-Menten model was found to best describe the pharmacokinetics of GB223, and the absorption rate of GB223 differed between males (0.0146 h-1) and females (0.0081 h-1). Serum C-terminal telopeptide of type I collagen decreased significantly postdose, and the inhibition lasted 42-168 days. No deaths or drug-related serious adverse events occurred. The most frequent adverse events were blood parathyroid hormone increased (94.1%), blood phosphorus decreased (67.6%) and blood calcium decreased (58.8%). In the GB223 group, 44.1% (15/34) of subjects were antidrug antibody positive after dosing. CONCLUSION: In this study, we demonstrated for the first time that a single subcutaneous injection of GB223, from 7 to 140 mg, is safe and well tolerated in healthy Chinese subjects. GB223 has a nonlinear pharmacokinetic profile, and sex was a potential covariate that may affect the absorption rate of GB223. CLINICAL TRIAL REGISTRATION: NCT04178044 and ChiCTR1800020338.

A Sleep-Specific Midbrain Target for Sevoflurane Anesthesia.

Sevoflurane has been the most widely used inhaled anesthetics with a favorable recovery profile; however, the precise mechanisms underlying its anesthetic action are still not completely understood. Here the authors show that sevoflurane activates a cluster of urocortin 1 (UCN1+ )/cocaine- and amphetamine-regulated transcript (CART+ ) neurons in the midbrain involved in its anesthesia. Furthermore, growth hormone secretagogue receptor (GHSR) is highly enriched in sevoflurane-activated UCN1+ /CART+ cells and is necessary for sleep induction. Blockade of GHSR abolishes the excitatory effect of sevoflurane on UCN1+ /CART+ neurons and attenuates its anesthetic effect. Collectively, their data suggest that anesthetic action of sevoflurane necessitates the GHSR activation in midbrain UCN1+ /CART+ neurons, which provides a novel target including the nucleus and receptor in the field of anesthesia.

A novel use of 3D-printed template in vaginal HDR brachytherapy.

PURPOSE: The High-Dose-Rate (HDR) vaginal cylinder treatment is typically designed using the initial CT, while the subsequent implants are verified using rudimentary methods (i.e., visual inspection, ruler measurements, etc.) and/or X-ray imaging. We are proposing the use of a 3D-printed individualized template that could provide simple and reproducible vaginal cylinder insertion. MATERIAL AND METHODS: Six patients were included in the study with prescriptions of 6 Gy/fraction for 2 to 5 fractions (total 27 treatments). The first 1 to 2 treatments were delivered without the template and the rest with the CT-based 3D-printed templates. Cone beam CTs (CBCTs) were acquired to verify the cylinder placement for all treatments. D2cc of the bladder and rectum are recorded on both planning CT and the following on-treatment CBCTs. RESULTS: By using the templates, the tip position variation on average (±1 SD) reduced from 0.8±0.5 cm to 0.6±0.4 cm, and angular difference decreased from 5.3±3.5° to 4.7±2.4°. The pitch and yaw deviation are reduced from 0.9 ± 5.8° and 0.4±2.9° to 0.0±3.9° and -0.2±3.0°, respectively. The deviation of D2cc to bladder from the plan reduced from 6±4% to 5±3%, and rectum from 5±2% to 4±4%. CONCLUSION: The 3D-printed patient-specific cylinder templates could potentially improve the geometrical reproducibility of cylinder treatments at no cost of additional imaging. The D2cc for the bladder and rectum are determined by the treatment length rather than their respective volumes.

Machine learning-assisted ensemble analysis for the prediction of urinary tract infection in elderly patients with ovarian cancer after cytoreductive surgery.

BACKGROUND: Urinary tract infection (UTI) is a common type of postoperative infection following cytoreductive surgery for ovarian cancer, which severely impacts the prognosis and quality of life of patients. AIM: To develop a machine learning assistant model for the prevention and control of nosocomial infection. METHODS: A total of 674 elderly patients with ovarian cancer who were treated at the Department of Gynaecology at Jingzhou Central Hospital between January 31, 2016 and January 31, 2022 and met the inclusion criteria of the study were selected as the research subjects. A retrospective analysis of the postoperative UTI and related factors was performed by reviewing the medical records. Five machine learning-assisted models were developed using two-step estimation methods from the candidate predictive variables. The robustness and clinical applicability of each model were assessed using the receiver operating characteristic curve, decision curve analysis and clinical impact curve. RESULTS: A total of 12 candidate variables were eventually included in the UTI prediction model. Models constructed using the random forest classifier, support vector machine, extreme gradient boosting, and artificial neural network and decision tree had areas under the receiver operating characteristic curve ranging from 0.776 to 0.925. The random forest classifier model, which incorporated factors such as age, body mass index, catheter, catheter intubation times, blood loss, diabetes and hypoproteinaemia, had the highest predictive accuracy. CONCLUSION: These findings demonstrate that the machine learning-based prediction model developed using the random forest classifier can be used to identify elderly patients with ovarian cancer who may have postoperative UTI. This can help with treatment decisions and enhance clinical outcomes.

High-dose-rate interstitial brachytherapy vs external beam radiation for the treatment of complex keloids.

Postoperative external beam radiation therapy (EBRT) with superficial X-rays or electrons and high-dose-rate brachytherapy (HDR BT) are both viable options for managing keloid scars. However, complex keloid scars are especially challenging to manage. We aim to compare the benefit and challenges between interstitial HDR BT and electron EBRT in treating the complex keloids. Three patients with 7 complex keloids: 3 jaw lines, 1 postauricular, 1 posterior neck, and 2 chest walls are included in this study. All patients are treated to 6 Gy x 3 fractions with HDR BT using the flexible interstitial catheters, and electron EBRT plans were created retrospectively for dosimetric comparison. The average D90 is 21.8 ± 8.3 Gy (1 SD) (121%) and 16.9 ± 1.9 Gy (1SD) (94%) in HDR and EBRT plans, respectively. The average treatment time was 7 minutes per patient (range: 6 - 8.5 minutes) for the HDR BT. Dosimetric comparison reveals that HDR plans provide superior coverage to the keloid scars than the EBRT plans. Clinical workflow is streamlined with HDR procedures. The cosmetic outcome with the interstitial HDR BT is satisfactory.

Erratum: RNA interference-mediated depletion of TRPM8 enhances the efficacy of epirubicin chemotherapy in prostate cancer LNCaP and PC3 cells.

[This corrects the article DOI: 10.3892/ol.2018.7847.].

Vaginal oligometastatic disease of colorectal primary: Report of a novel therapeutic approach.

Vaginal oligometastatic disease of colorectal primary is a rare malignancy with few reported cases in the literature and no standardized treatment paradigm. We report on the definitive management of an unusual case of an elderly woman with the aforementioned disease. A 78-year-old African-American woman presented with vaginal spotting and was found to have a vaginal lesion. Final pathology was consistent with moderately differentiated adenocarcinoma of colorectal primary. Extensive work up, which included endoscopies, pathologic analyzes, and imaging workup, did not reveal a primary gastrointestinal malignancy. The patient underwent partial vaginectomy and final pathology once again confirmed moderately differentiated adenocarcinoma of colorectal primary (CDX 2 and CEA positive, ER/PR, and CK 7 negative) with negative margins. She went on to receive adjuvant concurrent chemoradiation with 5-FU based chemotherapy. She received 45 Gy in 25 fractions to the whole pelvis followed by an HDR brachytherapy boost to 12 Gy in two fractions. Unfortunately, 10 months after completing radiation, she was found to have adenocarcinoma arising from a hepatic flexure colon polyp on colonoscopy. She required definitive surgical resection and was staged as mpT3N0M1. She received 12 cycles of 5-FU and at 2-year follow-up was found to be disease free with no evidence of locoregional recurrence or distant metastatic disease. Continued long-term follow up is warranted.

Quantitative Medical Physics National Job Data Distribution Analysis.

PURPOSE: The purpose of this study was to investigate the contemporary distribution of medical physics (MP) employment opportunities across the United States. METHODS AND MATERIALS: An annual record (2018-2019) of advertised full-time MP jobs was created using publicly available information from the American Association of Physicists in Medicine and Indeed websites. Listed jobs were categorized based on position name, work experience, job function, and geographic region. To account for regional population differences, a preponderance of employment opportunities per 10 million people was computed. Using Commission on Accreditation of Medical Physics Education Programs residency accreditation data, the nationwide locations of the MP training centers and the number of residency positions per annum were identified. A chi-square goodness-of-fit test was used for statistical analysis. RESULTS: A total of 441 unique MP jobs were identified nationwide per annum (2018-2019). The highest percentage of MP jobs was reported from the South region (33.6%), and the lowest (17.2%) was from the West. Analysis revealed that 148 jobs (33.6%) were academic and 293 (66.4%) were nonacademic. The South had the most academic jobs overall (31.8%), whereas the West had the fewest (13.5%). Regionally, the highest percentage of academic jobs (46.9%) was reported from the Northeast, whereas the West had the lowest percentage (26.3%). The analysis of academic versus nonacademic job comparison by regions showed statistically significant differences (P = .0133). The Midwest and the West regions, respectively, showed the highest (18.2) and lowest (10.24) number of jobs per unit population, measured in 10 million. CONCLUSIONS: To our knowledge, this is one of the first national quantitative job data analyses of MP job distributions. This study revealed the level of demand for qualified candidates in 2018 to 2019, showing an imbalance between academic and nonacademic positions across the regions of the United States. Moreover, the geographic distribution of job listings deviated significantly from expectation given the relative population of each region.