https://www.excli.de/index.php/excli/issue/feedEXCLI Journal2024-02-01T10:08:18+01:00EXCLI Journalexcli@ifado.deOpen Journal Systems<center><img class="img-responsive" src="/public/site/images/lindemann/Lucida_logo_neu_geschrieben.PNG" alt="EXCLI Journal Logo"></center> <p>EXCLI Journal publishes original research reports, authoritative reviews and case reports of experimental and clinical sciences.</p> <div class="toggleBox"><input id="toggleContent" name="toggleContent" type="checkbox"> <label class="open" for="toggleContent">More...</label> <label class="close" for="toggleContent">Less...</label> <div> <p><strong>EXCLI Journal </strong>(eISSN 1611-2156) is particularly keen to keep a broad view of science and technology, and therefore welcomes papers which bridge disciplines and may not suit the narrow specialism of other journals. Although the general emphasis is on biological sciences, studies from the following fields are explicitly encouraged:</p> <p>Immunology, toxicology, ergonomics, neurosciences, psychology, occupational medicine, clinical and preclinical studies, drug development, pharmacology, environmental health, chemistry including analytical chemistry, biochemistry, cell biology, genetics, forensic medicine, oncology and cancer research, proteomics, systems biology, hepatology and gastroenterology, aging research, psychiatric research, behavioral sciences.</p> </div> </div>https://www.excli.de/index.php/excli/article/view/6700Empowering personalized medicine 2023-10-19T12:21:28+02:00Oliwia PiwockaWiktoria M. SuchorskaKatarzyna Kulcenty<p class="Abstract">In recent decades, significant progress has been made in understanding the molecular characteristics of cancer and its microenvironment, leading to the development of life-saving treatments. However, patients often experience side effects from standard therapies, highlighting the need for personalized medicine. Personalized medicine aims to customize drug therapy and preventive care based on individual patients' specific requirements. The heterogeneity within tumors and among patients necessitates personalized medicine approaches. Patient-derived organoids (PDOs), xenografts (PDXs), and explants (PDEs) have emerged as valuable models for studying tumor behaviour and drug response. This paper aims to summarize the latest advancements in patient-derived explants, focusing on their potential utility in the clinic. Different methods for culturing PDEs, including the free-floating approach, the grid method, and sponge scaffolds, are discussed. These approaches provide opportunities for long-term viability, oxygen and nutrient supply, and maintenance of tissue integrity. Additionally, various solid tumor models using PDEs are highlighted, together with assays to study PDE viability, characteristics, and response to drug treatment.</p>2024-01-10T00:00:00+01:00Copyright (c) 2024 Oliwia Piwocka, Wiktoria M. Suchorska, Katarzyna Kulcentyhttps://www.excli.de/index.php/excli/article/view/6760Overall review of curative impact and barriers of CAR-T cells in osteosarcoma2023-11-01T07:00:26+01:00Guilin LiHong WangVafa Meftahpour<p class="Abstract">Osteosarcoma (OS) is a rare form of cancer and primary bone malignancy in children and adolescents. Current therapies include surgery, chemotherapy, and amputation. Therefore, a new therapeutic strategy is needed to dramatically change cancer treatment. Recently, chimeric antigen receptor T cells (CAR-T cells) have been of considerable interest as it has provided auspicious results and patients suffering from low side effects after injection that resolve with current therapy. However, there are reports that cytokine release storm (CRS) can be observed in some patients. In addition, as researchers have faced problems that limit and suppress T cells, further studies are required to resolve these problems. In addition, to maximize the therapeutic benefit of CAR-T cell therapy, researchers have suggested that combination therapy could be better used to treat cancer by overcoming any problems and reducing side effects as much as possible. This review summarizes these problems, barriers, and the results of some studies on the evaluation of CAR-T cells in patients with osteosarcoma.</p>2024-03-06T00:00:00+01:00Copyright (c) 2024 Guilin Li, Hong Wang, Vafa Meftahpourhttps://www.excli.de/index.php/excli/article/view/6972Plasticity and resistance of cancer stem cells as a challenge for innovative anticancer therapies – do we know enough to overcome this?2024-01-11T15:54:10+01:00Agnieszka Knopik-SkrockaAlicja SempowiczOliwia Piwocka<p class="Abstract">According <span style="color: black;">to the</span> CSC hypothesis, cancer stem cells are pivotal in initiating, developing, and causing cancer recurrence. Since the identification of CSCs in leukemia, breast cancer, glioblastoma, and colorectal cancer in the 1990s, researchers have actively investigated the origin and biology of CSCs. However, the CSC hypothesis and the role of these cells in tumor development model is still in debate. These cells exhibit distinct surface markers, are capable of self-renewal, demonstrate unrestricted proliferation, and display metabolic adaptation. CSC phenotypic plasticity and the capacity to EMT is strictly connected to the stemness state. CSCs show high resistance to <span style="color: black;">chemotherapy, radiotherapy,</span> and immunotherapy. The plasticity of CSCs is significantly influenced by <span style="color: black;">tumor</span> microenvironment factors, <span style="color: black;">such as</span> hypoxia. Targeting the genetic and epigenetic changes of cancer cells, <span style="color: black;">together</span> <span style="color: black;">with</span> interactions with the <span style="color: black;">tumor</span> microenvironment, presents promising avenues for therapeutic strategies.</p>2024-02-29T00:00:00+01:00Copyright (c) 2024 Agnieszka Knopik-Skrocka, Alicja Sempowicz, Oliwia Piwockahttps://www.excli.de/index.php/excli/article/view/6489Molecular targeted therapies for cutaneous squamous cell carcinoma2023-11-30T09:29:44+01:00Harpreet SinghHitesh ChopraInderbir SinghSourav MohantoMohammed Gulzar AhmedShruti GhumraAnmol SeelanManisha SurvaseArvind KumarAmrita MishraArun Kumar MishraMohammad Amjad Kamal<p class="Abstract">Cutaneous Squamous Cell Carcinoma (cSCC) is a common and potentially fatal type of skin cancer that poses a significant threat to public health and has a high prevalence rate. Exposure to ultraviolet radiation on the skin surface increases the risk of cSCC, especially in those with genetic syndromes like xerodermapigmentosum and epidermolysis bullosa. Therefore, understanding the molecular pathogenesis of cSCC is critical for developing personalized treatment approaches that are effective in cSCC. This article provides a comprehensive overview of current knowledge of cSCC pathogenesis, emphasizing dysregulated signaling pathways and the significance of molecular profiling. Several limitations and challenges associated with conventional therapies, however, are identified, stressing the need for novel therapeutic strategies. The article further discusses molecular targets and therapeutic approaches, i.e., epidermal growth factor receptor inhibitors, hedgehog pathway inhibitors, and PI3K/AKT/mTOR pathway inhibitors, as well as emerging molecular targets and therapeutic agents. The manuscript explores resistance mechanisms to molecularly targeted therapies and proposes methods to overcome them, including combination strategies, rational design, and optimization. The clinical implications and patient outcomes of molecular-targeted treatments are assessed, including response rates and survival outcomes. The management of adverse events and toxicities in molecular-targeted therapies is crucial and requires careful monitoring and control. The paper further discusses future directions for therapeutic advancement and research in this area, as well as the difficulties and constraints associated with conventional therapies.</p>2024-02-27T00:00:00+01:00Copyright (c) 2024 Harpreet Singh, Hitesh Chopra, Inderbir Singh, Sourav Mohanto, Mohammed Gulzar Ahmed, Shruti Ghumra, Anmol Seelan, Manisha Survase, Arvind Kumar, Amrita Mishra, Arun Kumar Mishra, Mohammad Amjad Kamalhttps://www.excli.de/index.php/excli/article/view/6975Diagnostic utility of RAS mutation testing for refining cytologically indeterminate thyroid nodules2024-02-01T10:08:18+01:00Isabel R. RiccioAlexandra C. LaFortezaMohammad H. HusseinJoshua P. LinhuberPeter P. IssaJonathan StaavManal Said FawzyEman A. ToraihEmad Kandil<p class="Abstract"><em>RAS</em> mutations are prevalent in indeterminate thyroid nodules, but their association with malignancy risk and utility for diagnosis remains unclear. We performed a systematic review and meta-analysis to establish the clinical value of <em>RAS</em> mutation testing for cytologically indeterminate thyroid nodules. PubMed and Embase were systematically searched for relevant studies. Thirty studies comprising 13,328 nodules met the inclusion criteria. Random effects meta-analysis synthesized pooled estimates of <em>RAS</em> mutation rates, risk of malignancy with <em>RAS</em> positivity, and histologic subtype outcomes. The pooled mutation rate was 31 % (95 % CI 19-44 %) among 5,307 indeterminate nodules. N<em>RAS</em> mutations predominated at 67 % compared to H<em>RAS</em> (24 %) and K<em>RAS</em> (12 %). The malignancy rate with <em>RAS</em> mutations was 58 % (95 %CI=48-68 %). <em>RAS</em> positivity increased malignancy risk 1.7-fold (RR 1.68, 95 %CI=1.21-2.34, p=0.002), with significant between-study heterogeneity (I2=89 %). Excluding one outlier study increased the relative risk to 1.75 (95 %CI=1.54-1.98) and I2 to 14 %. Funnel plot asymmetry and Egger's test (p=0.03) indicated potential publication bias. Among <em>RAS</em>-positive malignant nodules, 38.6 % were follicular variant papillary carcinoma, 34.1 % classical variant, and 23.2 % follicular carcinoma. No statistically significant difference in the odds of harboring <em>RAS</em> mutation was found between subtypes. In conclusion, <em>RAS</em> mutation testing demonstrates clinical utility for refining the diagnosis of cytologically indeterminate thyroid nodules. Positivity confers a 1.7-fold increased malignancy risk, supporting use for personalized decision-making regarding surgery vs. monitoring. Follicular variant papillary carcinoma constitutes the most common <em>RAS</em>-positive malignant histological subtype.</p>2024-02-15T00:00:00+01:00Copyright (c) 2024 Isabel R. Riccio, Alexandra C. Laforteza, Mohammad H. Hussein, Joshua P. Linhuber, Peter P. Issa, Jonathan Staav, Manal S. Fawzy, Eman A. Toraih, Emad Kandilhttps://www.excli.de/index.php/excli/article/view/6868Niosome as a promising tool for increasing the effectiveness of anti-inflammatory compounds2023-12-06T20:43:07+01:00Mohammad Saleh FadaeiMohammad Reza FadaeiAmir Emad KheiriehPouria Rahmanian-DevinMohammad Mahdi DabbaghiKiarash Nazari TavallaeiAbouzar ShafaghiHooman HatamiVafa Baradaran RahimiAli NokhodchiVahid Reza Askari<p class="Abstract">Niosomes are drug delivery systems with widespread applications in pharmaceutical research and the cosmetic industry. Niosomes are vesicles of one or more bilayers made of non-ionic surfactants, cholesterol, and charge inducers. Because of their bilayer characteristics, similar to liposomes, niosomes can be loaded with lipophilic and hydrophilic cargos. Therefore, they are more stable and cheaper in preparation than liposomes. They can be classified into four categories according to their sizes and structures, namely small unilamellar vesicles (SUVs), large unilamellar vesicles (LUVs,), multilamellar vesicles (MLVs), and multivesicular vesicles (MVVs). There are many methods for niosome preparation, such as thin-film hydration, solvent injection, and heating method. The current study focuses on the preparation methods and pharmacological effects of niosomes loaded with natural and chemical anti-inflammatory compounds in kinds of literature during the past decade. We found that most research was carried out to load anti-inflammatory agents like non-steroidal anti-inflammatory drugs (NSAIDs) into niosome vesicles. The studies revealed that niosomes could improve anti-inflammatory agents' physicochemical properties, including solubility, cellular uptake, stability, encapsulation, drug release and liberation, efficiency, and oral bioavailability or topical absorption.</p>2024-02-07T00:00:00+01:00Copyright (c) 2024 Mohammad Saleh Fadaei, Mohammad Reza Fadaei, Amir Emad Kheirieh, Pouria Rahmanian-Devin, Mohammad Mahdi Dabbaghi, Kiarash Nazari Tavallaei, Abouzar Shafaghi, Hooman Hatami, Vafa Baradaran Rahimi, Ali Nokhodchi, Vahid Reza Askarihttps://www.excli.de/index.php/excli/article/view/6885Efficacy of automated fasteners versus hand-tied knots in cardiac surgery2023-12-13T17:41:12+01:00Zoaib Habib TharwaniMuhammad Abdul QadeerAli AbdullahRubab AliMuhammad Ahmed ChaudharyShurjeel Uddin QaziSameh M. Said<p>Valve surgery is common in cardiac procedures, with fasteners like COR-KNOT® and hand-tied knots used for knot securing. This study compares their efficacy in valve surgery patients. We searched PubMed, SCOPUS, and Cochrane Central until August 2023. Outcomes assessed included aortic cross-clamp time (AXT), cardiopulmonary bypass (CPB) time, valvular regurgitation, mortality, prolonged ventilatory support, atrial fibrillation, postoperative left ventricular ejection fraction (LVEF), and renal failure. Subgroup analysis was performed for minimally invasive and open cardiac surgery. We used a random effects model for analysis. We included eight observational studies and two randomized controlled trials (RCTs) with a total of 1.411 participants. COR-KNOT significantly reduced AXT [MD -15.14, 95 % CI (-18.57, -11.70), P<0.00001] and CPB time [MD -12.38, 95 % CI (-14.99, -9.77), P<0.00001]. Valvular regurgitation [RR 0.40, 95 % CI (0.26, 0.61), P<0.0001] and need for prolonged ventilatory support [RR 0.29, 95 % CI (0.13, 0.65), P=0.003] were significantly lower with COR-KNOT. There were no significant differences in mortality [RR 0.39, 95 % CI (0.09, 1.69), P=0.44], atrial fibrillation [RR 1.03, 95 % CI (0.83, 1.27), P=0.81], LVEF changes [MD 0.05, 95 % CI (−1.37, 1.47), P = 0.95], or renal failure [RR 0.87, 95 % CI (0.16, 4.80), P = 0.87]. COR-KNOT devices reduce operative time and valvular regurgitation without increasing mortality or adverse outcomes. This supports their use in enhancing surgical efficiency and patient outcomes. However, ongoing discussions about suturing techniques, especially in minimally invasive procedures, highlight the need for further research and consensus among practitioners.</p>2024-02-06T00:00:00+01:00Copyright (c) 2024 Zoaib Habib Tharwani, Muhammad Abdul Qadeer, Ali Abdullah, Rubab Ali, Muhammad Ahmed Chaudhary, Shurjeel Uddin Qazi, Sameh M. Saidhttps://www.excli.de/index.php/excli/article/view/6747Exploring the vast potentials and probable limitations of novel and nanostructured implantable drug delivery systems for cancer treatment2023-10-31T10:40:07+01:00Maryam EbrahimniaSonia AlaviHamed VaeziMahdieh Karamat-IradmousaAzadeh Haeri<p class="Abstract">Conventional cancer chemotherapy regimens, albeit successful to some extent, suffer from some significant drawbacks, such as high-dose requirements, limited bioavailability, low therapeutic indices, emergence of multiple drug resistance, off-target distribution, and adverse effects. <a name="_Hlk118709991"></a>The main goal of developing implantable drug delivery systems (IDDS) is to address these challenges and maintain anti-cancer drugs directly at the intended sites of therapeutic action while minimizing inevitable side effects. IDDS possess numerous advantages over conventional drug delivery, including controlled drug release patterns, one-time drug administration, as well as loading and stabilizing poorly water-soluble chemotherapy drugs. Here, we summarized conventional and novel (three-dimensional (3D) printing and microfluidic) preparation techniques of different IDDS, including nanofibers, films, hydrogels, wafers, sponges, and osmotic pumps. These systems could be designed with high biocompatibility and biodegradability features using a wide variety of natural and synthetic polymers. We also reviewed the published data on these systems in cancer therapy with a particular focus on their release behavior. Various release profiles could be attained in IDDS, which enable predictable, adjustable, and sustained drug releases. Furthermore, multi-step or stimuli-responsive drug release could be obtained in these systems. The studies mentioned in this article have proven the effectiveness of IDDS for treating different cancer types with high prevalence, including breast cancer, and aggressive cancer types, such as glioblastoma and liver cancer. Additionally, the challenges in applying IDDS for efficacious cancer therapy and their potential future developments are also discussed. Considering the high potential of IDDS for further advancements, such as programmable release and degradation features, further clinical trials are needed to ensure their efficiency. The overall goal of this review is to expand our understanding of the behavior of commonly investigated IDDS and to identify the barriers that should be addressed in the pursuit of more efficient therapies for cancer.</p>2024-02-01T00:00:00+01:00Copyright (c) 2024 Maryam Ebrahimnia, Sonia Alavi, Hamed Vaezi, Mahdieh Karamat-Iradmousa, Azadeh Haerihttps://www.excli.de/index.php/excli/article/view/6767Plasma amino acids in major depressive disorder2023-11-20T06:58:55+01:00Omar GammohAlaa AljabaliMurtaza M. Tambuwala<p>Addressing the formidable challenge posed by the development of effective and personalized interventions for major depressive disorder (MDD) necessitates a comprehensive comprehension of the intricate role that plasma amino acids play and their implications in MDD pathology and pharmacology. Amino acids, owing to their indispensable functions in neurotransmission, metabolism, and immune regulation, emerge as pivotal entities in this intricate disorder. Our primary objective entails unraveling the underlying mechanisms and unveiling tailored treatments through a meticulous investigation into the interplay between plasma amino acids, MDD, and pharmacological strategies. By conducting a thorough and exhaustive review of the existing literature, we have identified pertinent studies on plasma amino acids in MDD, thereby uncovering noteworthy disturbances in the profiles of amino acids among individuals afflicted by MDD when compared to their healthy counterparts. Specifically, disruptions in the metabolism of tryptophan, phenylalanine, and tyrosine, which serve as precursors to essential neurotransmitters, have emerged as prospective biomarkers and critical contributors to the pathophysiology of depression. Amnio acids play an essential role in MDD and could represent an attractive pharmacological target, more studies are further required to fully reveal their underlying mechanisms.</p>2024-01-04T00:00:00+01:00Copyright (c) 2024 Omar Gammoh, Alaa Aljabali, Murtaza M. Tambuwalahttps://www.excli.de/index.php/excli/article/view/6553Unraveling NEAT1's complex role in lung cancer biology2023-11-07T09:01:33+01:00Md Sadique HussainObaid AfzalGaurav GuptaAhsas GoyalWaleed Hassan AlmalkiImran KazmiSami I. AlzareaAbdulmalik Saleh Alfawaz AltamimiNeelam KukretiAmlan ChakrabortySachin Kumar SinghKamal Dua<p class="Abstract">This review delves into the pivotal role of the long non-coding RNA NEAT1 in cancer biology, particularly in lung cancer (LC). It emphasizes NEAT1's unique subcellular localization and active involvement in gene regulation and chromatin remodeling. The review highlights NEAT1's impact on LC development and progression, including cell processes such as proliferation, migration, invasion, and resistance to therapy, positioning it as a potential diagnostic marker and therapeutic target. The complex web of NEAT1's regulatory interactions with proteins and microRNAs is explored, alongside challenges in targeting it therapeutically. The review concludes optimistically, suggesting future avenues for research and personalized LC therapies, shedding light on NEAT1's crucial role in LC.</p>2024-01-03T00:00:00+01:00Copyright (c) 2024 Md Sadique Hussain, Obaid Afzal, Gaurav Gupta, Ahsas Goyal, Waleed Hassan Almalki, Imran Kazmi, Sami I. Alzarea, Abdulmalik Saleh Alfawaz Altamimi, Neelam Kukreti, Amlan Chakraborty, Sachin Kumar Singh, Kamal Duahttps://www.excli.de/index.php/excli/article/view/6740Myocardial infarct size is reduced by nitrite and nitrate administration2023-12-05T08:30:12+01:00Younes YassaghiSajad JeddiKhosrow KashfiAsghar Ghasemi<p>Ischemic heart disease (IHD) is the leading cause of mortality worldwide and can be complicated by myocardial infarction (MI), leading to cardiac failure. Inorganic nitrite and nitrate, which release nitric oxide (NO), can protect the heart against myocardial injury. This animal systematic review and meta-analysis aims to assess whether the administration of nitrite/nitrate decreases myocardial infarct size. We systematically searched PubMed, Scopus, and Web of Science databases until October 2023; 15 eligible animal studies (35 study arms for in-vivo and 10 for in-vitro studies) published between 1989 and 2023 were included. <em>In-vivo</em> studies were conducted on rats, mice, cats, and dogs, and <em>in-vitro</em> studies on rats and mice with an overall exposure of 0.03 to 12713 mg/kg to nitrate/nitrite administrated before, after, or during ischemia mainly by intravenous single bolus or by oral over 270 days. All <em>in-vitro</em> studies used nitrite/nitrate before ischemia, with the concentration ranging between 0.34 to 201 μM. MI was induced by occlusion of the left anterior diagonal or left circumflex arteries in <em>in-vitro</em> studies and by isoproterenol in <em>in-vivo</em> studies. Infarct size was measured by direct staining of the sliced heart sections. In <em>in-vivo</em> studies, nitrite (overall effect size (ES)=-17.0 %, 95 % confidence interval (CI)=-21.3, -12.8, P<0.001) and nitrate (overall ES= -9.6 %, 95 % CI=-15.7, -3.4, P=0.002) reduced myocardial infarct size. In <em>in-vitro</em> studies, nitrite (overall ES=-15.8 %, 95 % CI=-25.5, -6.2, P=0.001) reduced the infarct size. Sensitivity analysis showed that the overall effect of nitrite on myocardial infarct size was unaffected by doses or health conditions in <em>in-vivo</em> and <em>in-vitro</em> studies. In conclusion, our meta-analysis showed that nitrite/nitrate administration can effectively reduce myocardial infarct size. However, these results should be approached with caution because of the limitations of animal studies and the existing high heterogeneity.</p>2024-01-03T00:00:00+01:00Copyright (c) 2024 Younes Yassaghi, Sajad Jeddi, Khosrow Kashfi, Asghar Ghasemihttps://www.excli.de/index.php/excli/article/view/6809Celecoxib-induced acute generalized exanthematous pustulosis 2023-11-15T15:05:13+01:00Abul Hasan Shadali Abdul KhaderMeenu Singh<p class="Abstract">Celecoxib, a selective COX-2 inhibitor, and non-selective anti-inflammatory drug, is commonly prescribed as the first-line analgesic for osteoarthritis, rheumatoid arthritis, and certain acute pain cases. It is mainly preferred for its lower risk of gastrointestinal adverse effects. However, it also carries risks, including renal and liver toxicity, anaphylaxis, and Stevens-Johnson syndrome. A rare but severe cutaneous adverse reaction associated with celecoxib is Acute Generalized Exanthematous Pustulosis (AGEP), characterized by extensive nonfollicular sterile pustules on an erythematous background, fever, and neutrophilic leukocytosis. AGEP is a rare condition with an incidence rate of 1-5 cases per million per year in the general population. It is primarily triggered by drugs, with antibiotics accounting for over 90 % of cases<span style="color: #212529;">. Here, we present the case of a 44-year-old female who presented with a sudden, rapidly progressive, painful, pruritic rash all over her body with associated leukocytosis. A skin biopsy confirmed the presence of a pustular rash. The patient reported taking Celebrex (celecoxib) for worsening arthritis two weeks prior to symptom onset. The patient was diagnosed with Celecoxib-induced AGEP based on clinical and histopathological features. Treatment involved steroid therapy and discontinuation of NSAIDs (</span>non-steroidal anti-inflammatory drugs)<span style="color: #212529;">. Encouragingly, the patient's rash improved within three days. Our case report aims to raise awareness of AGEP as a side effect of NSAIDs. Although AGEP is not typically serious, it can be fatal in elderly patients. Therefore, prompt identification and immediate cessation of the culprit drug is crucial.</span></p>2024-01-24T00:00:00+01:00Copyright (c) 2024 Abul Hasan Shadali Abdul Khader, Meenu Singhhttps://www.excli.de/index.php/excli/article/view/6404hsa-miR-34a-5p enhances temozolomide anti-tumoral effects on glioblastoma2024-01-22T07:49:16+01:00Mahdi Abdoli ShadbadAmir BaghbanzadehBehzad Baradaran<p class="Abstract">Glioblastoma multiform (GBM) is a commonly diagnosed brain neoplasm with a poor prognosis. Accumulating evidence has highlighted the significance of microRNA (miR) dysregulation in tumor development and progression. This study investigated the effect of hsa-miR-34a-5p and its combination with temozolomide on GBM, the related molecular mechanisms, and the signaling pathway using <em>in-silico</em> and <em>in-vitro</em> approaches. The <em>in-silico</em> tumor bulk and single-cell RNA sequencing analyses were done on TCGA-GTEx, CGGA, GSE13276, GSE90603, and GSE182109 datasets. After selecting the A172 cell line, hsa-miR-34a-5p mimics were transfected, and the cell viability, migration, cell cycle, clonogenicity, and apoptosis of studied groups were studied using MTT, scratch, flow cytometry, colony formation, and Annexin V/PI assays. The mRNA expression of <em>CASP9</em>, <em>CASP3</em>, <em>CASP8</em>, <em>MMP2</em>, <em>CD44</em>, <em>CDK6</em>, <em>CDK4</em>, <em>CCND1</em>, <em>RAF1</em>, <em>MAP2K1</em>, <em>MET</em>, <em>SRC</em>, and <em>CD274</em> was studied using qRT-PCR method. hsa-miR-34a-5p downregulated <em>RAF1 </em>expression, as the signaling factor of the MAPK pathway. The combined treatment significantly downregulated the expression of <em>MET</em>, <em>SRC</em>, and <em>MAP2K1</em>, leading to the inhibition of the MET/MAPK pathway compared to temozolomide. Besides exerting anti-tumoral effects on the cell viability, migration, cell cycle, apoptosis, and clonogenicity of A172 cells, its combination with temozolomide enhanced temozolomide anti-tumoral effect. Compared to temozolomide, the combined treatment significantly decreased <em>CDK4</em>, <em>CDK6</em>, <em>CCND1</em>, and <em>MMP2</em> expression. hsa-miR-34a-5p targets <em>RAF1</em>, as the signaling factor of the MAPK pathway, and potentiates the temozolomide anti-tumoral effect on A172 cells.</p>2024-03-13T00:00:00+01:00Copyright (c) 2024 Mahdi Abdoli Shadbad, Amir Baghbanzadeh, Behzad Baradaranhttps://www.excli.de/index.php/excli/article/view/6804Pre-emptive paracetamol reduces intra-operative opioid use in patients undergoing day-case oncologic breast surgery2023-11-14T23:09:42+01:00Daniah AlsaadiLyndon LowJames TingMichael CraughwellJohn McDonnellAoife LoweryKarl Sweeney<p>Minimization of intra-operative opioid use is an area of ongoing research interest with several potential benefits to the patient. Pre-emptive analgesia, defined as the administration of an analgesic before surgery to prevent establishment of central sensitization of pain, is one avenue that has been explored to achieve this. A retrospective observational study was undertaken to examine the effect of pre-emptive paracetamol on intra-operative opioid requirements. The medical and operative data of 156 patients who underwent day-case wide local excision and sentinel lymph node biopsy with and without regional block surgery at our center between October 2019 and May 2022 was carried out. Data were collected on demographics, total intra-operative and immediate post-operative opioid consumption. 57 patients did not receive pre-emptive paracetamol while 90 did. Baseline characteristics were similar. Our results showed a statistically significant reduction in morphine (p <0.029) and remifentanil (p <0.007) consumption in patients who received a regional block and pre-emptive paracetamol. Those who did not receive a regional block and were given pre-emptive paracetamol had a decrease in OxyNorm (p <0.022) requirements. A combination of general anesthesia (GA), regional block and pre-emptive paracetamol reduced intra-operative consumption of Fentanyl, OxyNorm, diclofenac, dexketoprofen, and clonidine (P <0.001) when compared to just GA alone. Use of pre-emptive paracetamol in reduction of intra-operative opioid requirements showed promising results but larger studies may strengthen the evidence for this association. A multimodal analgesic approach that utilizes pre-emptive paracetamol can be a viable method to decrease intra-operative of analgesic requirements.</p>2024-02-29T00:00:00+01:00Copyright (c) 2024 Daniah Alsaadi, Lyndon Low, James Ting, Michael Craughwell, John McDonnell, Aoife Lowery, Karl Sweeneyhttps://www.excli.de/index.php/excli/article/view/6785Metabolomic analysis of the human placenta reveals perturbations in amino acids, purine metabolites, and small organic acids in spontaneous preterm birth2023-12-18T11:31:08+01:00Eva CifkovaRona KarahodaJaroslav StranikCilia AbadMarian KacerovskyMiroslav LisaFrantisek Staud<p class="Abstract">Spontaneous preterm delivery presents one of the most complex challenges in obstetrics and is a leading cause of perinatal morbidity and mortality. Although it is a common endpoint for multiple pathological processes, the mechanisms governing the etiological complexity of spontaneous preterm birth and the placental responses are poorly understood. This study examined placental tissues collected between May 2019 and May 2022 from a well-defined cohort of women who experienced spontaneous preterm birth (n = 72) and healthy full-term deliveries (n = 30). Placental metabolomic profiling of polar metabolites was performed using Ultra-High Performance Liquid Chromatography/Mass Spectrometry (UHPLC/MS) analysis. The resulting data were analyzed using multi- and univariate statistical methods followed by unsupervised clustering. A comprehensive metabolomic evaluation of the placenta revealed that spontaneous preterm birth was associated with significant changes in the levels of 34 polar metabolites involved in intracellular energy metabolism and biochemical activity, including amino acids, purine metabolites, and small organic acids. We found that neither the preterm delivery phenotype nor the inflammatory response explain the reported differential placental metabolome. However, unsupervised clustering revealed two molecular subtypes of placentas from spontaneous preterm pregnancies exhibiting differential enrichment of clinical parameters. We also identified differences between early and late preterm samples, suggesting distinct placental functions in early spontaneous preterm delivery. Altogether, we present evidence that spontaneous preterm birth is associated with significant changes in the level of placental polar metabolites. Dysregulation of the placental metabolome may underpin important (patho)physiological mechanisms involved in preterm birth etiology and long-term neonatal outcomes.</p>2024-02-13T00:00:00+01:00Copyright (c) 2024 Eva Cifkova, Rona Karahoda, Jaroslav Stranik, Cilia Abad, Marian Kacerovsky, Miroslav Lisa, Frantisek Staudhttps://www.excli.de/index.php/excli/article/view/6621Immunoaffinity proteomics for kidney injury biomarkers in male beagle dogs2023-12-08T10:04:20+01:00Wael NaboulsiHannes PlanatscherFelix F. SchmidtAndreas SteinhilberThomas O. JoosAdeyemi O. AdedejiJames Eric McDuffieOliver Pötz<p>Drug-induced kidney injury (DIKI) is a cause of drug development failure. Dogs represent a common non-rodent animal model in pre-clinical safety studies; however, biomarker assays for detecting nephrotoxicity in dogs are limited. To identify novel proteins and gain insight into the molecular mechanisms involved in DIKI, we developed an assay to evaluate proteomic changes associated with DIKI in male beagle dogs that received nephrotoxic doses of tobramycin for 10 consecutive days. Label-free quantitative discovery proteomics analysis on representative kidney cortex tissues collected on Day 11 showed that the tobramycin-induced kidney injury led to a significant differential regulation of 94 proteins mostly associated with mechanisms of nephrotoxicity such as oxidative stress and proteasome degradation. For verification of the proteomic results, we developed a multiplex peptide-centric immunoaffinity liquid chromatography tandem mass spectrometry assay (IA LC-MS/MS) to evaluate the association of eight DIKI protein biomarker candidates using kidney cortices collected on Day 11 and urine samples collected on Days -4, 1, 3, 7 and 10. The results showed that most biomarkers evaluated were detected in the kidney cortices and their expression profile in tissue aligned with the label-free data. Cystatin C was the most consistent marker regardless of the magnitude of the renal injury while fatty acid-binding protein-4 (FABP4) and kidney injury molecule-1 (KIM-1) were the most affected biomarkers in response to moderate proximal tubular injury in absence of changes in serum-based concentrations of blood urea nitrogen or creatinine. In the urine, clusterin is considered the most consistent biomarker regardless of the magnitude and time of the renal injury. To our knowledge, this is the most comprehensive multiplex assay for the quantitative analysis of mechanism-based proximal tubular injury biomarkers in dogs.</p>2024-02-05T00:00:00+01:00Copyright (c) 2024 Wael Naboulsi, Hannes Planatscher, Felix F. Schmidt, Andreas Steinhilber, Thomas O. Joos, Adeyemi O. Adedeji, James Eric McDuffie, Oliver Pötzhttps://www.excli.de/index.php/excli/article/view/6777Resistance band training with functional electrical stimulation improves force control capabilities in older adults2023-12-20T05:51:54+01:00Joon Ho LeeHanall LeeHyunJoon KimRye-Kyeong KimTae Lee LeeDo-Kyung KoHajun LeeNyeonju Kang<p class="Abstract">Resistance band training (RBT) with functional electrical stimulation (FES) may be an effective exercise regimen for improving age-related motor impairments. This preliminary study investigated the potential effects of bimanual RBT with FES on upper limb motor functions in older adults. This study randomly assigned 22 elderly people to the bimanual RBT with FES (Bi-RBT+FES) group and the RBT without FES (Bi-RBT) group. All participants performed isometric hand-grip force control tasks in unimanual (dominant and non-dominant) and bimanual conditions before and after four weeks of exercise for each group. We quantified the mean force, force accuracy, force variability, and force regularity at two targeted force levels (i.e., 10 % and 40 % of maximum voluntary contraction; MVC) to estimate changes in force control capabilities. The results revealed that the Bi-RBT+FES group demonstrated a greater force accuracy in the dominant hand at 10 % of MVC after training. Non-dominant hands in the Bi-RBT+FES group increased force accuracy at 40 % of MVC and reduced force variability collapsed across two targeted force levels. Both groups showed a decrease in force regularity after training. These preliminary results indicate that Bi-RBT+FES may be a viable option to facilitate functional recovery of the upper limbs in older adults.</p>2024-01-26T00:00:00+01:00Copyright (c) 2024 Joon Ho Lee, Hanall Lee, HyunJoon Kim, Rye-Kyeong Kim, Tae Lee Lee, Do-Kyung Ko, Hajun Lee, Nyeonju Kanghttps://www.excli.de/index.php/excli/article/view/6710Minocycline declines interleukin-1β-induced apoptosis and matrix metalloproteinase expression in C28/I2 chondrocyte cells2023-11-16T09:29:31+01:00Amin MoqadamiMohammad Khalaj-KondoriMohammad Ali Hosseinpour FeiziBehzad Baradaran<p>Osteoarthritis (OA) is a degenerative joint disease that occurs with aging. In its late phases, it is determined by the loss of chondrocytes and the breakdown of the extracellular matrix, resulting in pain and functional impairment. Interleukin-1 beta (IL-1β) is increased in the injured joints and contributes to the OA pathobiology by inducing chondrocyte apoptosis and up-regulation of matrix metalloproteinases (MMPs). Here, we aimed to understand whether minocycline could protect chondrocytes against the IL-1β-induced effects. The human C28/I2 chondrocyte cell line was treated with IL-1β or IL-1β plus minocycline. Cell viability/toxicity, cell cycle progression, and apoptosis were assessed with MMT assay and flow cytometry. Expression of apoptotic genes and MMPs were evaluated with qRT-PCR and western blotting. IL-1β showed a significant cytotoxic effect on the C28/I2 chondrocyte cells. The minocycline effective concentration (EC<sub>50</sub>) significantly protected the C28/I2 cells against the IL-1β-induced cytotoxic effect. Besides, minocycline effectively lowered IL-1β-induced sub-G1 cell population increase, indicating the minocycline anti-apoptotic effect. When assessed by real-time PCR and western blotting, the minocycline treatment group showed an elevated level of Bcl-2 and a significant decrease in the mRNA and protein expression of the apoptotic markers Bax and Caspase-3 and Matrix metalloproteinases (MMPs) such as MMP-3 and MMP-13. In conclusion, IL-1β promotes OA by inducing chondrocyte death and MMPs overexpression. Treatment with minocycline reduces these effects and decreases the production of apoptotic factors as well as the MMP-3 and MMP-13. Minocycline might be considered as an anti-IL-1β therapeutic supplement in the treatment of osteoarthritis.</p>2024-01-24T00:00:00+01:00Copyright (c) 2024 Amin Moqadami, Mohammad Khalaj-Kondori, Mohammad Ali Hosseinpour Feizi, Behzad Baradaranhttps://www.excli.de/index.php/excli/article/view/6496Adjunctive transcranial direct current stimulation to improve swallowing functions in Parkinson's disease2023-11-07T08:12:17+01:00Ali Akbar DashteleiMichael A. NitscheMohammad Ali SalehinejadAmir Hassan HabibiJalal BakhtyiariAhmad Reza Khatoonabadi<p>Swallowing problems are frequent in Parkinson's disease (PD). The aim of this study was to determine the effectiveness of combined transcranial Direct Current Stimulation (tDCS) and Conventional Dysphagia Therapy (CDT) on dysphagia in PD patients. Twenty PD patients with dysphagia were randomized into two groups: combination therapy (anodal tDCS plus CDT) and sham tDCS combined with CDT. Anodal or sham tDCS, bilaterally over the pharyngeal motor cortex, was applied with one mA during the first 20 min (real) or 30 s (sham) of CDT, which was delivered for 30 min. Both groups received twice-daily treatment sessions within two weeks. Swallowing functions were evaluated before, immediately, and one month after the intervention via the Penetration-Aspiration Scale (PAS), and the Swallowing Disorder Questionnaire (SDQ) as the primary outcome measures, and the Dysphagia Handicap Index (DHI) as the secondary outcome measure. The results showed a significant improvement of PAS scores from baseline to post-intervention and baseline to follow-up in both groups without significant differences between groups (t=0.03, p=0.973, and t=1.27, p=0.22 for post-intervention and follow-up time points, respectively). The results showed a significant reduction of SDQ and DHI scores in both groups after the intervention, but the magnitude of the change was significantly larger in the anodal tDCS group at the post-intervention (ta=2.58, <em>pa</em>=0.019 and tb=2.96, <em>pb</em>=0.008) and follow-up (ta=2.65, <em>pa</em>=0.016 and tb=2.97, <em>pb</em>=0.008) time points. This study provides preliminary evidence that bi-hemispheric anodal tDCS combined with CDT enhances swallowing functions in patients with Parkinson's disease more than CDT alone.</p>2024-01-18T00:00:00+01:00Copyright (c) 2024 Ali Akbar Dashtelei, Michael A. Nitsche, Mohammad Ali Salehinejad, Amir Hassan Habibi, Jalal Bakhtyiari, Ahmad Reza Khatoonabadihttps://www.excli.de/index.php/excli/article/view/6705AZU1: a new promising marker for infection in orthopedic and trauma patients?2023-12-05T07:57:45+01:00Philipp HemmannLisa KloppenburgRegina BreinbauerSabrina EhnertGunnar BlumenstockMarie K. ReumannFelix ErneJohann JazewitschTobias SchwarzHeiko BaumgartnerTina HistingMika RollmannAndreas K. Nüssler<p class="Abstract">Early and reliable detection of infection is vital for successful treatment. Serum markers such as C-reactive protein (CRP) and procalcitonin (PCT) are known to increase with a time lag. Azurocidin 1 (AZU1) has emerged as a promising marker for septic patients, but its diagnostic value in orthopedic and trauma patients remains unexplored. Between July 2020 and August 2023, all patients necessitating inpatient treatment for periprosthetic joint infection (PJI), peri-implant infection (II), soft tissue infection, chronic osteomyelitis, septic arthrodesis, bone non-union with and without infection were enrolled. Patients undergoing elective total joint arthroplasty (TJA) served as the control group. Blood samples were collected and analyzed for CRP, white blood cell count (WBC), PCT, and AZU1. Based on the inclusion and exclusion criteria 222 patients were included in the study (trauma = 38, soft tissue infection = 75, TJA = 33, PJI/II = 39, others = 37). While sensitivity and specificity were comparably high for AZU1 (0.734/0.833), CRP and PCT had higher specificity (0.542/1 and 0.431/1, respectively), and WBC a slightly higher sensitivity (0.814/0.455) for septic conditions. Taken together, the area under the curve (AUC) showed the highest accuracy for AZU1 (0.790), followed by CRP (0.776), WBC (0.641), and PCT (0.656). The Youden-Index was 0.57 for AZU1, 0.54 for CRP, 0.27 for WBC, and 0.43 for PCT. Elevated AZU1 levels effectively distinguished patients with a healthy condition from those suffering from infection. However, there is evidence suggesting that trauma may influence the release of AZU1. Additional research is needed to validate the diagnostic value of this new biomarker and further explore its potential clinical applications.</p>2024-01-03T00:00:00+01:00Copyright (c) 2024 Philipp Hemmann, Lisa Kloppenburg, Regina Breinbauer, Sabrina Ehnert, Gunnar Blumenstock, Marie K. Reumann, Felix Erne, Johann Jazewitsch, Tobias Schwarz, Heiko Baumgartner, Tina Histing, Mika Rollmann, Andreas K. Nüsslerhttps://www.excli.de/index.php/excli/article/view/6442Impairment of value-based decision-making in morphine-dependent rats is partly related to neural connectivity between the anterior cingulate cortex and basolateral amygdala2023-11-27T07:01:45+01:00Zahra FatahiMohammad FatahiAbbas Haghparast<p>Previous studies have established that the amygdala specifically the basolateral amygdala (BLA), has a fundamental role in decision-making. The present study aimed to investigate functional and neural synchronization between the BLA and anterior cingulate cortex (ACC) while making effort-choice decisions regarding pre-morphine dependence and morphine dependence times. A T-maze decision-making task with a differential outlay (great vs. small effort) and benefit (great vs. small reward) was done, and local field potentials from the BLA and ACC were assessed simultaneously. Results illustrated that in pre-morphine dependence time, when the animals made great reward/great effort decisions, there was a neural synchronization between both regions in beta and gamma frequency bands; and also, in delta, theta, beta, and gamma frequencies while expending effort and climbing the barrier. However, in morphine-dependent rats, during low reward/low effort choice and also during expending low effort, there was just a weak neural coherence in gamma frequency. Besides, there was neural synchronization in theta, beta, and gamma frequencies during reaching great reward in pre-morphine dependence time. Nevertheless, during reaching low reward in morphine dependence time, there was a weaker coherence in beta and gamma compared to pre-morphine dependence. These findings showed that functional and neural coherence between the BLA and ACC has a fundamental role in making the effort-based decision and expending effort. Preference for low reward/low effort, and decrease in expending effort in morphine-dependent rats is partly associated with the changes in the neural coherence between the BLA and ACC.</p>2024-01-03T00:00:00+01:00Copyright (c) 2024 Zahra Fatahi, Mohammad Fatahi , Abbas Haghparasthttps://www.excli.de/index.php/excli/article/view/6641Uniting minds and methods2023-10-10T08:53:05+02:00Pallav SenguptaSulagna Dutta2024-01-12T00:00:00+01:00Copyright (c) 2024 Pallav Sengupta, Sulagna Duttahttps://www.excli.de/index.php/excli/article/view/6857Roles of the quantification of serine in the brain2023-12-02T10:46:31+01:00Jia-Meng LiYa-Zhi BaiShuang-Qing Zhang2024-01-05T00:00:00+01:00Copyright (c) 2024 Jia-Meng Li, Ya-Zhi Bai, Shuang-Qing Zhang