Bortezomib exerts its anti-cancer activity through the regulation of Skp2/p53 axis in non-melanoma skin cancer cells and C. elegans.

Non-melanoma skin cancer (NMSC), encompassing basal and squamous cell carcinoma, is the most prevalent cancer in the United States. While surgical removal remains the conventional therapy with a 95% 5-year cure rate, there is a growing interest in exploring alternative treatment strategies. In this study, we investigated the role of Bortezomib (BTZ), a proteasome inhibitor, in NMSC. Using two NMSC cell lines (A431 and A388), we examined the effects of BTZ treatment. Our results demonstrated that 48 h of BTZ treatment led to downregulating Skp2 expression in both A431 and A388 cells while upregulating p53 expression, specifically in A388 cells. These alterations resulted in impaired cellular growth and caspase-dependent cell death. Silencing Skp2 in A388 cells with siRNA confirmed the upregulation of p53 as a direct target. Furthermore, BTZ treatment increased the Bax to Bcl-2 ratio, promoting mitochondrial permeability and the subsequent release of cytochrome C, thereby activating caspases. We also found that BTZ exerted its antitumor effects by generating reactive oxygen species (ROS), as blocking ROS production significantly reduced BTZ-induced apoptotic cell death. Interestingly, BTZ treatment induced autophagy, which is evident from the increased expression of microtubule-associated proteins nucleoporin p62 and LC-3A/B. In addition to cell lines, we assessed the impact of BTZ in an in vivo setting using Caenorhabditis elegans (C. elegans). Our findings demonstrated that BTZ induced germline apoptosis in worms even at low concentrations. Notably, this increased apoptosis was mediated through the activity of CEP-1, the worm's counterpart to mammalian p53. In summary, our study elucidated the molecular mechanism underlying BTZ-induced apoptosis in NMSC cell lines and C. elegans. By targeting the skp2/p53 axis, inducing mitochondrial permeability, generating ROS, and promoting autophagy, BTZ demonstrates promising anti-cancer activity in NMSC. These findings provide novel insights into potential therapeutic strategies for controlling the unregulated growth of NMSC.

Most Major Hospitals Fail to Comply with Federal Price Transparency Regulations.

PURPOSE: This study aims to present hospital compliance with federal price transparency regulations for sports medicine procedures. METHODS: Online price estimator and machine-readable files were recovered for U.S. News and World Report's (USNWR) top 100 orthopedic hospitals. From June to November 2023, compliance and monetary values were recorded for each of Centers for Medicare and Medicaid Services (CMS) price transparency regulations. Price estimator data was assessed based on hospital placement in the bottom and top 50 of the 100 institutions under review, as well as by region (Northeast, South, Midwest, West). Statistical analyses included two-sample t-tests and Kruskal Wallis tests. RESULTS: 95% of hospitals had a price estimator tool for both subacromial decompression (Current Procedural Terminology (CPT): 29826) and meniscectomy (CPT: 29881). Only 38% were compliant with all regulations for subacromial decompression and 39% for meniscectomy; the remaining did not list minimum or maximum procedure charges. Higher ranked hospitals were significantly more likely to charge a higher cash price for subacromial decompression and meniscectomy (p = 0.040 and p = 0.009 respectively). Compliance with machine-readable file reporting was poor with less than 20% meeting requirements for each CPT code. Reported prices varied greatly by hospital. CONCLUSIONS: This study demonstrates that USNWR top 100 orthopedic hospitals exhibit poor overall compliance with federal price transparency regulations for sports medicine procedures. Most often they lack full compliance by not reporting minimum or maximum charges as part of their price estimator tool or do not report procedure prices in their machine-readable files. Hospitals also exhibit wide variation in prices reported for specific procedures. CLINICAL RELEVANCE: Consumer price transparency continues to be an important goal in healthcare as it allows patients to make informed decisions when selecting appropriate treatment options and providers. To realize the full benefits of price transparency hospitals should address areas of improvement.

Results of Randomized Controlled Trials of Platelet-Rich Plasma in Lower-Extremity Tendinopathy Are Not Influenced by Industry Sponsorship.

PURPOSE: To determine whether industry affiliation influences the results of randomized controlled trials (RCTs) studying the use of platelet-rich plasma (PRP) for the treatment of patellar or Achilles tendinopathy. METHODS: The PubMed, Scopus, Cochrane, and MEDLINE databases were searched in July 2023 for RCTs investigating PRP for the treatment of patellar or Achilles tendinopathy published between 2009 and July 2023. Industry affiliation was determined by analyzing each study's funding or conflict-of-interest section. Author disclosures were searched in the American Academy of Orthopaedic Surgeons disclosure database and the Centers for Medicare & Medicaid Services open payments database. An industry-affiliated (IA) designation was given if an author had a relevant disclosure or if the company that funded the study manufactured PRP. Otherwise, a non-industry-affiliated (NIA) designation was given. Fisher exact analysis was used to determine whether PRP had a favorable effect, no significant effect, or an unfavorable effect on outcome. RESULTS: Analysis was performed on 22 studies (10 IA and 12 NIA), with 17 studies (77.3%) reporting a conflict of interest or funding for the research, 4 (18.2%) reporting no conflict of interest, and 1 (4.5%) with no reporting. Of the 22 included studies, 8 (36.4%) reported favorable outcomes regarding PRP use and 14 (63.6%) reported no significant effect. Favorable outcomes were found in 4 of the 10 IA studies (40.0%), whereas no significant effect was reported in 6 (60.0%). The 12 NIA studies included 4 (33.3%) with favorable results and 8 (66.7%) with no significant effect. The comparison between industry affiliation and results reported was not statistically significant (P > .999). CONCLUSIONS: The results of RCTs evaluating the use of PRP in lower-extremity tendinopathy were not influenced by industry sponsorship. CLINICAL RELEVANCE: Most biomedical research is funded through industry sponsorship. Although this relation is necessary as technologies are developed, it is important to scrutinize studies for evidence of industry bias to understand how this bias may be affecting study results published in the literature.

Perioperative Intravenous Dexamethasone Use Is Not Associated with Periprosthetic Joint Infection or Wound Healing Complications Following Shoulder Arthroplasty.

BACKGROUND: Perioperative intravenous (IV) dexamethasone is commonly used in lower extremity total joint arthroplasty to manage postoperative pain and nausea/vomiting, and recent studies have demonstrated that its use may lower rates of acute postoperative medical complications. However, there is limited information regarding the safety and efficacy of IV dexamethasone in patients undergoing total shoulder arthroplasty (TSA). Additionally, there is concern surrounding corticosteroid use prior to surgery as preoperative corticosteroid injections have been associated with adverse outcomes after TSA, including periprosthetic joint infection (PJI) and revision surgery. Thus, the purpose of this study was to evaluate the effect of perioperative IV dexamethasone on 90-day rates of PJI, wound complications, and medical complications after TSA. METHODS: The Premiere national hospital database was used to identify adult patients undergoing elective TSA between 2016 and 2020; patients were excluded if they were under 18 years old, were undergoing revision TSA, or had a prior proximal humerus open reduction internal fixation (ORIF) procedure. Patients who did and did not receive perioperative IV dexamethasone were then compared in both univariate and multivariate analyses. A Bonferroni correction was utilized to adjust for multiple comparisons. The primary endpoint was risk of acute infectious complications within 90 days of surgery, including PJI and wound infection/dehiscence. Secondary endpoints included acute pulmonary, renal, and thromboembolic complications. RESULTS: A total of 135,333 patients underwent TSA during the study period; 61.2% underwent reverse total shoulder arthroplasty (RTSA), 33.8% underwent anatomic total shoulder arthroplasty (ATSA), and 5.0% underwent hemiarthroplasty (HA). From 2016 to 2020, perioperative IV dexamethasone use increased by 135%. Multivariate analysis revealed that patients who received perioperative IV dexamethasone did not have increased odds of PJI, superficial wound infection, or wound dehiscence (p = 0.15 - 0.47) but did have decreased odds of sepsis (OR 0.67, 95% CI 0.55-0.81) and other medical complications such as urinary tract infection (UTI) and acute kidney injury (AKI). Additionally, there was a trend towards decreased 90-day hospital readmission (OR 0.88, 95% CI 0.81-0.96, p=0.003). CONCLUSIONS: Perioperative IV dexamethasone was not associated with increased risk of acute infectious and wound healing complications. Moreover, patients who received perioperative IV dexamethasone had decreased odds of medical complications and trended towards lower rates of 90-day hospital readmission. The results of this study support the safety of perioperative IV dexamethasone use in patients undergoing elective TSA.

Proteomic insight towards key modulating proteins regulated by the aryl hydrocarbon receptor involved in ovarian carcinogenesis and chemoresistance.

Gynecological malignancies pose a severe threat to female lives. Ovarian cancer (OC), the most lethal gynecological malignancy, is clinically presented with chemoresistance and a higher relapse rate. Several studies have highly correlated the incidence of OC to exposure to environmental pollutants, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a process mainly mediated through activating the aryl hydrocarbon receptor (AhR). We have previously reported that exposure of OC cells to TCDD, an AhR activator, significantly modulated the expression of several genes that play roles in stemness and chemoresistance. However, the effect of AhR activation on the whole OC cell proteome aiming at identifying novel druggable targets for both prevention and treatment intervention purposes remains unrevealed. For this purpose, we conducted a comparative proteomic analysis of OC cells A2780 untreated/treated with TCDD for 24 h using a mass spectrometry-based label-free shotgun proteomics approach. The most significantly dysregulated proteins were validated by Western blot analysis. Our results showed that upon AhR activation by TCDD, out of 2598 proteins identified, 795 proteins were upregulated, and 611 were downregulated. STRING interaction analysis and KEGG-Reactome pathway analysis approaches identified several significantly dysregulated proteins that were categorized to be involved in chemoresistance, cancer progression, invasion and metastasis, apoptosis, survival, and prognosis in OC. Importantly, selected dysregulated genes identified by the proteomic study were validated at the protein expression levels by Western blot analysis. In conclusion, this study provides a better understanding of the the cross-talk between AhR and several other molecular signaling pathways and the role and involvement of AhR in ovarian carcinogenesis and chemoresistance. Moreover, the study suggests that AhR is a potential therapeutic target for OC prevention and maintenance. SIGNIFICANCE: To our knowledge, this is the first study that investigates the role and involvement of AhR and its regulated genes in OC by performing a comparative proteomic analysis to identify the critical proteins with a modulated expression upon AhR activation. We found AhR activation to play a tumor-promoting and chemoresistance-inducing role in the pathogenesis of OC. The results of our study help to devise novel therapeutics for better management and prevention and open the doors to finding novel biomarkers for the early detection and prognosis of OC.

Comparison of Ultrasound and MRI with Intraoperative Findings in the Diagnosis of Peroneal Tendinopathy, Tears, and Subluxation.

Suspected peroneal tendinopathy, tears, and subluxation are often confirmed preoperatively using magnetic resonance imaging (MRI) or diagnostic ultrasound (US). No study has directly compared the accuracy of these tests for the diagnosis of peroneal tendon pathology. The purpose of this study is to directly compare MRI and US to intraoperative findings in patients who underwent surgery for suspected peroneal pathology to determine the imaging diagnostic accuracy. Operative records and diagnostic images for 21 consecutive patients who had both MRI and US prior to surgery for suspected peroneal tendinopathy, tears, or subluxation were retrospectively reviewed. The results of this review are compared with the intraoperative findings to yield the sensitivity and specificity for each imaging modality. For the diagnosis of peroneal tendon tears, US was found to have a sensitivity of 88% and specificity of 100%, compared to 100% sensitivity and specificity for MRI. In the diagnosis of peroneal tendinopathy, both US and MRI had a sensitivity and specificity of 100%. In diagnosing peroneal subluxation, US was 100% sensitive compared to 66% for MRI, and both were 100% specific. In conclusion, US was found to be more effective in diagnosing peroneal subluxation and MRI was slightly more accurate in the diagnosis of peroneal tendon tears.

Sanguinarine Triggers Apoptosis in Cutaneous Squamous Cell Carcinoma Cells through Reactive Oxygen Species-Dependent c-Jun N-Terminal Kinase Signaling Pathway.

BACKGROUND: The benzophenanthridine Sanguinarine (Sng) is one of the most abundant root alkaloids with a long history of investigation and pharmaceutical applications. The cytotoxicity of Sng against various tumor cells is well-established; however, its antiproliferative and apoptotic potential against the cutaneous squamous cell carcinoma (cSCC) cells remains unknown. In the present study, we investigated the anti-cancer potential of Sng against cSCC cells and elucidated the underlying mechanisms relevant to the drug action. METHODS: The inhibitory effect of Sng on cSCC cells was evaluated by analyzing cell viability, colony-forming ability and multi-caspase activity. Apoptosis was quantified through Annexin-V/Propidium iodide flow cytometric assay and antagonized by pan-caspase inhibitor z-VAD-FMK. Mitochondrial membrane potential (ΔΨm) dysfunction was analyzed by JC-1 staining, whereas reactive oxygen species (ROS) generation was confirmed by pretreatment with N-acetylcysteine (NAC) and fluorogenic probe-based flow cytometric detection. The expression of cell cycle regulatory proteins, apoptotic proteins and MAPK signaling molecules was determined by Western blotting. Involvement of JNK, p38-MAPK and MEK/ERK in ROS-mediated apoptosis was investigated by pretreatment with SP600125 (JNK inhibitor), SB203580 (p38 inhibitor) and U0126 (ERK1/2 inhibitor), respectively. The stemness-targeting potential of Sng was assessed in tumor cell-derived spheroids. RESULTS: Treatment with Sng decreased cell viability and colony formation in primary (A431) and metastatic (A388) cSCC cells in a time- and dose-dependent manner. Sng significantly inhibited cell proliferation by inducing sub-G0/G1 cell-cycle arrest and apoptosis in cSCC cells. Sng evoked ROS generation, intracellular glutathione (GSH) depletion, ΔΨm depolarization and the activation of JNK pathway as well as that of caspase-3, -8, -9, and PARP. Antioxidant NAC inhibited ROS production, replenished GSH levels, and abolished apoptosis induced by Sng by downregulating JNK. Pretreatment with z-VAD-FMK inhibited Sng-mediated apoptosis. The pharmacological inhibition of JNK by SP600125 mitigated Sng-induced apoptosis in metastatic cSCC cells. Finally, Sng ablated the stemness of metastatic cSCC cell-derived spheroids. CONCLUSION: Our results indicate that Sng exerts a potent cytotoxic effect against cSCC cells that is underscored by a mechanism involving multiple levels of cooperation, including cell-cycle sub-G0/G1 arrest and apoptosis induction through ROS-dependent activation of the JNK signaling pathway. This study provides insight into the potential therapeutic application of Sng targeting cSCC.

Exploring the in vivo anti-cancer potential of Neosetophomone B in leukemic cells using a zebrafish xenograft model.

Neosetophomone B (NSP-B) is a unique meroterpenoid fungal secondary metabolite that has previously demonstrated promising anti-cancer properties against various cancer cell lines in vitro. However, its in vivo anti-cancer potential remaines unexplored. To fill this gap in our knowledge, we tested NSP-B's in vivo anti-cancer activity using a zebrafish model, an organism that has gained significant traction in biomedical research due to its genetic similarities with humans and its transparent nature, allowing real-time tumor growth observation. For our experiments, we employed the K562-injected zebrafish xenograft model. Upon treating these zebrafish with NSP-B, we observed a marked reduction in the size and number of tumor xenografts. Delving deeper, our analyses indicated that NSP-B curtailed tumor growth and proliferation of leukemic grafted xenograft within the zebrafish. These results show that NSP-B possesses potent in vivo anti-cancer properties, making it a potential novel therapeutic agent for addressing hematological malignancies.

Non-coding RNAs in the epigenetic landscape of cutaneous T-cell lymphoma.

Cutaneous T-cell lymphoma (CTCL) is a type of cancer that affects skin, and is characterized by abnormal T-cells in the skin. Epigenetic changes have been found to play a significant role in the development and progression of CTCL. Recently, non-coding RNAs (ncRNAs), such as microRNAs and long non-coding RNAs, have been identified as key players in the regulation of gene expression in CTCL. These ncRNAs can alter the expression of genes involved in cell growth, differentiation, and apoptosis, leading to the development and progression of CTCL. In this review, we summarize the current understanding of the role of ncRNAs in CTCL, including their involvement in DNA methylation, and other biological processes. We also discuss the types of ncRNAs, their role as oncogenic or tumor suppressive, and their putative use as diagnostic and prognostic biomarkers, based on the emerging evidence from laboratory-based as well as patients-based studies. Moreover, we also present the potential targets and pathways affected by ncRNAs. A better understanding of the complex epigenetic landscape of CTCL, including the role of ncRNAs, has the potential to lead to the development of novel targeted therapies for this disease.

Embelin inhibits viability of cutaneous T cell lymphoma cell lines HuT78 and H9 by targeting inhibitors of apoptosis.

Cutaneous T cell lymphoma (CTCL) is a varied group of neoplasms that affects the skin. Acquired resistance against chemotherapeutic drugs and associated toxic side effects are limitations that warrant search for novel drugs against CTCL. Embelin (EMB) is a naturally occurring benzoquinone derivative that has gained attention owing to its anticancer pharmacological actions and nontoxic nature. We assessed the anticancer activity of EMB against CTCL cell lines, HuT78, and H9. EMB inhibited viability of CTCL cells in a dose-dependent manner. EMB activated extrinsic and intrinsic pathways of apoptosis as shown by the activation of initiator and executioner caspases. EMB-induced apoptosis also involved suppression of inhibitors of apoptosis, XIAP, cIAP1, and cIAP2. PARP cleavage and upregulation of pH2AX indicated DNA damage induced by EMB. In conclusion, we characterized a novel apoptosis-inducing activity of EMB against CTCL cells, implicating EMB as a potential therapeutic agent against CTCL.

Corruptive Reprograming of Macrophages into Tumor-Associated Macrophages: The Transcriptional, Epigenetic and Metabolic Basis.

The tumor microenvironment (TME) is an important place with regard to the growth and sustenance of tumor cells [...].

Proteomic Dissection of Exosome Cargo: Progress and Future Perspectives.

The interest in exosomes in cancer research and treatment has increased exponentially in the past few years [...].

Breaching the Fortress of Tumor Microenvironment to Control Cancer Metastasis.

As the primary cause of death for >90% of cancers, metastasis is the fourth and final stage of cancer during which cells gain the ability to leave their primary site, invade surrounding tissues, and disseminate to distant organs [...].

Understanding Breast-Cancer-Associated Fibroblasts and Their Epigenetic Activation to Unveil Novel Targets for Breast Cancer Therapy.

The review article 'Cancer-Associated Fibroblasts: Epigenetic Regulation and Therapeutic Intervention in Breast Cancer' by Lee et al [...].

Epigenetic m6A RNA Modification Reader YTHDF1 in Merkel Cell Carcinoma.

Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine cutaneous malignancy that commonly affects older individuals with a high mortality rate [...].

Flavonoids on the Frontline against Cancer Metastasis.

Metastasis is the leading cause of death in cancer patients [...].

A Breast Cancer Image Classification Algorithm with 2c Multiclass Support Vector Machine.

Breast cancer is the most frequent type of cancer in women; however, early identification has reduced the mortality rate associated with the condition. Studies have demonstrated that the earlier this sickness is detected by mammography, the lower the death rate. Breast mammography is a critical technique in the early identification of breast cancer since it can detect abnormalities in the breast months or years before a patient is aware of the presence of such abnormalities. Mammography is a type of breast scanning used in medical imaging that involves using x-rays to image the breasts. It is a method that produces high-resolution digital pictures of the breasts known as mammography. Immediately following the capture of digital images and transmission of those images to a piece of high-tech digital mammography equipment, our radiologists evaluate the photos to establish the specific position and degree of the sickness in the breast. When compared to the many classifiers typically used in the literature, the suggested Multiclass Support Vector Machine (MSVM) approach produces promising results, according to the authors. This method may pave the way for developing more advanced statistical characteristics based on most cancer prognostic models shortly. It is demonstrated in this paper that the suggested 2C algorithm with MSVM outperforms a decision tree model in terms of accuracy, which follows prior findings. According to our findings, new screening mammography technologies can increase the accuracy and accessibility of screening mammography around the world.

Gastric juice non-coding RNAs as potential biomarkers for gastric cancer.

Gastric cancer (GC), being one of the most common malignant human tumors, occupies the second position in the structure of mortality in men and women. High rates of morbidity and mortality in this pathology determine its extremely high clinical and social significance. Diagnosis and timely treatment of precancerous pathology is the main way to reduce morbidity and mortality, and early detection of GC and its adequate treatment improve prognosis. The ability to accurately predict the development of GC and start treatment on time, as well as the ability to determine the stage of the disease if the diagnosis is confirmed - non-invasive biomarkers can become the key to solving these and many other problems of modern medicine. One of the promising biomarkers being studied are non-coding RNAs, namely, miсroRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs). They are involved in a wide range of processes, including apoptosis, proliferation, differentiation, angiogenesis, which play a critical role in the development of GC oncogenesis. In addition, they are quite specific and stable due to their carriers (extracellular vesicles or Argonaute 2 protein) and can be detected in various human biological fluids, in particular gastric juice. Thus, miRNAs, lncRNAs, and circRNAs isolated from the gastric juice of GC patients are promising preventive, diagnostic and prognostic non-invasive biomarkers. This review article presents the characteristics of circulating or extracellular miRNAs, lncRNAs, and circRNAs in gastric juice, allowing their use in the GC preventive, diagnosis, prognosis and monitoring therapy.

Current Understanding of Flavonoids in Cancer Therapy and Prevention.

Cancer is a major cause of death worldwide, with multiple pathophysiological manifestations. In particular, genetic abnormalities, inflammation, bad eating habits, radiation exposure, work stress, and toxin consumption have been linked to cancer disease development and progression. Recently, natural bioactive chemicals known as polyphenols found in plants were shown to have anticancer capabilities, destroying altered or malignant cells without harming normal cells. Flavonoids have demonstrated antioxidant, antiviral, anticancer, and anti-inflammatory effects. Flavonoid type, bioavailability, and possible method of action determine these biological actions. These low-cost pharmaceutical components have significant biological activities and are beneficial for several chronic disorders, including cancer. Recent research has focused primarily on isolating, synthesizing, and studying the effects of flavonoids on human health. Here we have attempted to summarize our current knowledge of flavonoids, focusing on their mode of action to better understand their effects on cancer.

Role of circulating-tumor DNA in the early-stage non-small cell lung carcinoma as a predictive biomarker.

Lung cancer is one of the most common solid malignancies. Tissue biopsy is the standard method for accurately diagnosing lung and many other malignancies over decades. However, molecular profiling of tumors leads to establishing a new horizon in the field of precision medicine, which has now entered the mainstream in clinical practice. In this context, a minimally invasive complementary method has been proposed as a liquid biopsy (LB) which is a blood-based test that is gaining popularity as it provides the opportunity to test genotypes in a unique, less invasive manner. Circulating tumor cells (CTC) captivating the Circulating-tumor DNA (Ct-DNA) are often present in the blood of lung cancer patients and are the fundamental concept behind LB. There are multiple clinical uses of Ct-DNA, including its role in prognostic and therapeutic purposes. The treatment of lung cancer has drastically evolved over time. Therefore, this review article mainly focuses on the current literature on circulating tumor DNA and its clinical implications and future goals in non-small cell lung cancer.