Recent Progress In Diagnosis Research Articles

Pathogenesis and Treatment Strategy of Intracranial Aneurysm

Intracranial aneurysm (IA) is a common cerebrovascular disease. Rupture of intracranial aneurysm can lead to subarachnoid hemorrhage, which is characterized by high mortality and poor prognosis. Once onset, the disease develops rapidly, seriously threatening people's life and health. Because intracranial aneurysms start insidiously and don't have corresponding clinical symptoms until they rupture, many patients miss the best opportunity for treatment. Even if you visit the medical center in time, there will be corresponding complications during the treatment. In recent years, with the continuous improvement of molecular biotechnology, the diagnosis and treatment of intracranial aneurysms have made great progress. This article reviews the recent progress in diagnosis, pathogenesis and postoperative treatment of intracranial aneurysms.

Abstract 956: NCX 4040 and napabucasin synergistically inhibits stemness in human prostate cancer (PCa) cellular models and potently targets transgenic murine PCa cells via inducing oxidative stress

Abstract Prostate cancer (PCa) continues to have a substantial impact on men’s wellbeing and quality of life regardless of recent progress in diagnosis and treatments and it continues to have the second highest occurrence rate following lung cancer. The strategy of combination drug therapy has gradually become a valuable choice for treating various cancer types, addressing the heterogeneity within tumors, and surpassing the constraints of existing treatment methods. In our previous work, when we combined two drugs NCX 4040 (an oxidative stress inducer) and napabucasin (a STAT3 signaling inhibitor), we discovered that the combination treatment synergistically works to inhibit the malignant characteristics of human PCa cells. Also, the combination upregulated the cGAS-STING immunogenic pathway in PCa cells which could potentially activate the cancer-targeting cytotoxic T-cells. In the current study, we aimed at investigating the anti-stemness properties of the drug duo which can not only inhibit cancer cell differentiation but also can be effective in preventing cancer relapse. We used two cell lines i.e., BPH-Cd which served as a model of cadmium induced PCa and DU145 as a model of advanced PCa to examine the anti-stemness properties of the drug combination. Based on western-blot analysis, we found the downregulation of transcription factors such as Oct4, Sox2, Nanog, β-catenin and cell surface markers like CD44, CD133 and ALDHA1, which are responsible for stem-cell like properties. In addition, we have tested the combinatory anticancer effects in transgenic mouse derived PCa cell line (Myc-Cap) as a prelude to conduct future studies in FVB mouse syngeneic model to evaluate the tumor suppressive and the antitumor immunogenic responses of combination treatment as it activated cGAS-STING pathway. By performing the cell viability assay, we found that the IC50 value of NCX 4040 is ~10µM and that of napabucasin is ~1μM, however when used in combination, ~90% inhibition is seen at 10µM of NCX and 250nM of napabucasin dual treatment. The drug combination also showed synergy in inhibiting tumorigenicity in clonogenic assay and migratory potential in wound-healing assay. By investigating the ROS production, cell death and cell cycle mechanism using flow cytometric analysis, it was observed that the combination therapy synergistically induces cellular oxidative stress which causes cancer cells to undergo late apoptosis and halts the growth of Myc-Cap cells in G2M phase of cell cycle. In conclusion, our data suggests that combination therapy of NCX 4040 and napabucasin can be potential treatment strategy for PCa warranting further evaluation in in vivo models. Citation Format: Shrushti Shah, Gnanasekar Munirathinam. NCX 4040 and napabucasin synergistically inhibits stemness in human prostate cancer (PCa) cellular models and potently targets transgenic murine PCa cells via inducing oxidative stress [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 956.

Chitosan/Nanohydroxyapatite/Hydroxyethyl-cellulose-based printable formulations for local alendronate drug delivery in osteoporosis treatment

Osteoporosis is a silent bone disease and a growing health issue. Despite recent progress in diagnosis and treatment, effective therapeutic strategies are still needed. One of the possible solutions is the implantation of engineered drug-releasing scaffolds at the disease site. To boost this approach further, we aimed to develop printable materials (the inks) for the construction of patient-specific 3D scaffolds with drug-release capability. The inks were composed of chitosan – a natural osteoinductive polysaccharide, nanohydroxyapatite – a natural bone matrix ingredient improving mechanical properties, sodium alendronate – a bioactive drug, and hydroxyethyl-cellulose – a filler improving the printability. Printed scaffolds were crosslinked with citric acid or KOH. After coating with collagen and gelatin, they demonstrated biocompatibility with the adipose-derived mesenchymal stem cells and MG-63 cell line. They also showed a sustained release of alendronate for 50 days, causing a significant reduction in the expression of Cathepsin K, an osteoclast-specific gene marker, which indicates the osteoclast-inhibiting capacity of the coated scaffolds. This work demonstrates the potential of developed printable materials to find applications as cell and drug carriers for the treatment of osteoporosis.

Yeni Sentezlenen Potansiyel HIF İnhibitörlerinin Hipoksik Koşullarda Küçük Hücre Dışı Akciğer Kanseri Üzerindeki İnhibitör Etkilerinin Belirlenmesi

According to global estimates, there are 2.3 million new cases and 1.8 million fatalities due to lung cancer each year. Despite recent progress in diagnosis and treatment, persistent challenges highlight the urgent need for novel therapeutics and innovative approaches to combat lung cancer effectively. Accordingly, in the present study, we aimed to investigate the anticancer properties of potential inhibitors of HIF-1α, compound 7a and 7b. In the study, HTB-54 and BEAS-2B cell lines were used. MTT cell viability experiments were performed to determine the effect of newly synthesized HIF inhibitors 7a and 7b on cell viability under normoxic and hypoxic conditions. Quantitative expression levels of HIF1A were determined by real-time PCR approach. While the half maximum inhibitory concentration (IC50) of compound 7a in HTB-54 cells was 10.37 µM under normoxic conditions, it was found to be 10.63 µM under hypoxic conditions. The IC50 value of another HIF inhibitor 7b in HTB-54 cells was found to be 8.80 µM under normoxic conditions and 9.54 µM under hypoxic conditions. The expression level of HIF1A was found to be lower in cells exposed to compounds 7a and 7b under hypoxia compared to the control group. Conversely, in normoxia, HIF1A expression level in cells exposed to compound 7a increased 6.5-fold (p<0.0001) compared to the control group, while it was found to increase approximately 9-fold (p<0.0001) when exposed to 7b. Consequently, both compound 7a and 7b holds great promise for future therapeutic interventions to lung cancer.

Cardiac Involvement in Classical Organic Acidurias: Clinical Profile and Outcome in a Pediatric Cohort.

Cardiac involvement is reported in a significant proportion of patients with classical organic acidurias (OAs), contributing to disability and premature death. Different cardiac phenotypes have been described, among which dilated cardiomyopathy (DCM) is predominant. Despite recent progress in diagnosis and treatment, the natural history of patients with OAs remains unresolved, specifically with regard to the impact of cardiac complications. We therefore performed a retrospective study to address this issue at our Referral Center for Pediatric Inherited Errors of Metabolism. Sixty patients with OAs (propionic (PA), methylmalonic (MMA) and isovaleric acidemias and maple syrup urine disease) diagnosed from 2000 to 2022 were systematically assessed at baseline and at follow-up. Cardiac anomalies were found in 23/60 OA patients, all with PA or MMA, represented by DCM (17/23 patients) and/or acquired long QT syndrome (3/23 patients). The presence of DCM was associated with the worst prognosis. The rate of occurrence of major adverse cardiac events (MACEs) at 5 years was 55% in PA with cardiomyopathy; 35% in MMA with cardiomyopathy; and 23% in MMA without cardiomyopathy. Liver transplantation was performed in seven patients (12%), all with PA or MMA, due to worsening cardiac impairment, and led to the stabilization of metabolic status and cardiac function. Cardiac involvement was documented in about one third of children diagnosed with classical OAs, confined to PA and MMA, and was often associated with poor outcome in over 50%. Etiological diagnosis of OAs is essential in guiding management and risk stratification.

Identification of two anti-Candida antibodies associated with the survival of patients with candidemia.

Candidemia (bloodstream invasion by Candida species) is a major fungal disease in humans. Despite the recent progress in diagnosis and treatment, therapeutic options are limited and under threat of antimicrobial resistance. The disease mortality remains high (around 40%). In contrast with deep-seated invasive candidiasis, particularly that occurring in patients with hematologic malignancies and organ transplants, patients with candidemia are often not immunocompromised and therefore able to mount memory anticandidal immune responses, perhaps primed by Candida commensalism. We investigated antibody immunity in candidemia patients and report here on the ability of these patients to produce antibodies that react with Candida antigens. In particular, the patients with high titers of IgG reactive with two immunodominant, virulence-associated antigens (Als3 and MP65) had a higher 30-day survival. If confirmed by controlled, prospective clinical studies, our data could inform the development of antibody therapy to better treat a severe fungal infection such as candidiasis.

Recent Progress in the Diagnosis and Treatment of Melanoma and Other Skin Cancers

In this Special Issue, the reader will find nine papers regarding recent progress in diagnosis and treatment to optimize the clinical management of melanoma and non-melanoma skin cancer [...].

Neurofibromatosis 1 (von Recklinghausen Disease).

Neurofibromatosis 1 (NF1), also known as von Recklinghausen disease, is one of the most common neurocutaneous genetic disorders. Loss of function of the NF1 gene results in overactivation of the RAS/MAPK pathway, leading to neurocutaneous manifestations and osseous abnormalities. Because of medical progress, molecular testing for NF1 after genetic counseling is now available in Japan. In addition, revised diagnostic criteria for NF1 were proposed by NF1 experts of an international panel in 2021. Because the overall degree of severity and manifestations in each patient are not predictable, age-specific annual monitoring and patient education by a multidisciplinary team are important for the management of NF1. Although treatment of plexiform neurofibroma has been challenging, selumetinib (an oral selective MEK1/2 inhibitor), which targets a pathway downstream of RAS, was approved in 2022 for use in children with inoperable, symptomatic plexiform neurofibromas in Japan. This article summarizes recent progress in diagnosis, clinical characteristics, and treatment of various manifestations of NF1 and proposes the future direction required to resolve unmet needs in patients with NF1 in Japan.

Recent progress in diagnosis and treatment of Human African Trypanosomiasis has made the elimination of this disease a realistic target by 2030.

Human African Trypanosomiasis (HAT) is caused by unicellular flagellated protozoan parasites of the genus Trypanosoma brucei. The subspecies T. b. gambiense is mainly responsible for mostly chronic anthroponotic infections in West- and Central Africa, accounting for roughly 95% of all HAT cases. Trypanosoma b. rhodesiense results in more acute zoonotic infections in East-Africa. Because HAT has a two-stage pathogenesis, treatment depends on clinical assessment of patients and the determination whether or not parasites have crossed the blood brain barrier. Today, ultimate confirmation of parasitemia is still done by microscopy analysis. However, the introduction of diagnostic lateral flow devices has been a major contributor to the recent dramatic drop in T. b. gambiense HAT. Other techniques such as loop mediated isothermal amplification (LAMP) and recombinant polymerase amplification (RPA)-based tests have been published but are still not widely used in the field. Most recently, CRISPR-Cas technology has been proposed to improve the intrinsic diagnostic characteristics of molecular approaches. This will become crucial in the near future, as preventing the resurgence of HAT will be a priority and will require tools with extreme high positive and negative predicted values, as well as excellent sensitivity and specificity. As for treatment, pentamidine and suramin have historically been the drugs of choice for the treatment of blood-stage gambiense-HAT and rhodesiense-HAT, respectively. For treatment of second-stage infections, drugs that pass the blood brain barrier are needed, and melarsoprol has been effectively used for both forms of HAT in the past. However, due to the high occurrence of post-treatment encephalopathy, the drug is not recommended for use in T. b. gambiense HAT. Here, a combination therapy of eflornithine and nifurtimox (NECT) has been the choice of treatment since 2009. As this treatment requires IV perfusion of eflornithine, efforts were launched in 2003 by the drugs for neglected disease initiative (DNDi) to find an oral-only therapy solution, suitable for rural sub-Saharan Africa treatment conditions. In 2019 this resulted in the introduction of fexinidazole, with a treatment regimen suitable for both the blood-stage and non-severe second-stage T. b. gambiense infections. Experimental treatment of T. b. rhodesiense HAT has now been initiated as well.

Periorbital rash and scaly plaques in a 13-year–old boy

Periorbital rash and scaly plaques in a 13-year–old boy

Advances in the diagnosis and treatment of acute respiratory distress syndrome induced by pancreatitis

Acute pancreatitis (AP) is one of the common diseases of the digestive system mainly characterized by acute inflammation of the pancreas and acinar cell destruction, and it can often develop into severe acute pancreatitis (SAP). Acute respiratory distress syndrome (ARDS) is one of the most common and serious complications of SAP and a common cause of death in patients with SAP. In recent years, there have gained new understanding of the pathogenesis, diagnosis, and treatment of SAP-related ARDS, however, a variety of drugs that have been shown to prevent ARDS in SAP animal models have not improved the prognosis of SAP-related ARDS patients in clinical researches. At present, the treatment of SAP-related ARDS still follows the general treatment principles of ARDS, such as treatment of primary disease, lung protective ventilation strategy, prone position ventilation, early short-term use of neuromuscular blockers and extracorporeal membrane oxygenation (ECMO), and so on. However, the influence of high intra-abdominal pressure, intestinal function failure, abdominal incision, and drainage tube on the treatment measures should also be considered for patients with SAP-related ARDS. This article reviews the recent progress in diagnosis and treatment of SAP-related ARDS.

Progression and Trends in Virus from Influenza A to COVID-19: An Overview of Recent Studies.

Influenza is a highly known contagious viral infection that has been responsible for the death of many people in history with pandemics. These pandemics have been occurring every 10 to 30 years in the last century. The most recent global pandemic prior to COVID-19 was the 2009 influenza A (H1N1) pandemic. A decade ago, the H1N1 virus caused 12,500 deaths in just 19 months globally. Now, again, the world has been challenged with another pandemic. Since December 2019, the first case of a novel coronavirus (COVID-19) infection was detected in Wuhan. This infection has risen rapidly throughout the world; even the World Health Organization (WHO) announced COVID-19 as a worldwide emergency to ensure human health and public safety. This review article aims to discuss important issues relating to COVID-19, including clinical, epidemiological, and pathological features of COVID-19 and recent progress in diagnosis and treatment approaches for the COVID-19 infection. We also highlight key similarities and differences between COVID-19 and influenza A to ensure the theoretical and practical details of COVID-19.

Palmitoylated Proteins on AML-Derived Extracellular Vesicles Promote Myeloid-Derived Suppressor Cell Differentiation via TLR2/Akt/mTOR Signaling.

Acute myeloid leukemia (AML) represents the most common acute leukemia among adults. Despite recent progress in diagnosis and treatment, long-term outcome remains unsatisfactory. The success of allogeneic stem cell transplantation underscores the immunoresponsive nature of AML, creating the basis for further exploiting immunotherapies. However, emerging evidence suggests that AML, similar to other malignant entities, employs a variety of mechanisms to evade immunosurveillance. In light of this, T-cell inhibitory myeloid-derived suppressor cells (MDSC) are gaining interest as key facilitators of immunoescape. Accumulation of CD14+HLA-DRlow monocytic MDSCs has been described in newly diagnosed AML patients, and deciphering the underlying mechanisms could help to improve anti-AML immunity. Here, we report that conventional monocytes readily take-up AML-derived extracellular vesicles (EV) and subsequently undergo MDSC differentiation. They acquired an CD14+HLA-DRlow phenotype, expressed the immunomodulatory indoleamine-2,3-dioxygenase, and upregulated expression of genes characteristic for MDSCs, such as S100A8/9 and cEBPβ. The Akt/mTOR pathway played a critical role in the AML-EV-induced phenotypical and functional transition of monocytes. Generated MDSCs displayed a glycolytic switch, which rendered them more susceptible toward glycolytic inhibitors. Furthermore, palmitoylated proteins on the AML-EV surface activated Toll-like receptor 2 as the initiating event of Akt/mTOR-dependent induction of MDSC. Therefore, targeting protein palmitoylation in AML blasts could block MDSC accumulation to improve immune responses. SIGNIFICANCE: These findings indicate that targeting protein palmitoylation in AML could interfere with the leukemogenic potential and block MDSC accumulation to improve immunity.

Metabolomics profile in gastrointestinal cancers: Update and future perspectives.

Despite recent progress in diagnosis and therapy, gastrointestinal (GI) cancers remain one of the most important causes of death with a poor prognosis due to late diagnosis. Serum tumor markers and detection of occult blood in the stool are the current tests used in the clinic of GI cancers; however, these tests are not useful as diagnostic screening since they have low specificity and low sensitivity. Considering that one of the hallmarks of cancer is dysregulated metabolism and metabolomics is an optimal approach to illustrate the metabolic mechanisms that belong to living systems, is now clear that this -omics could open a new way to study cancer. In the last years, nuclear magnetic resonance (NMR) metabolomics has demonstrated to be an optimal approach for diseases' diagnosis nevertheless a few studies focus on the NMR capability to find new biomarkers for early diagnosis of GI cancers. For these reasons in this review, we will give an update on the status of NMR metabolomic studies for the diagnosis and development of GI cancers using biological fluids.

Inhalation Injury: Unmet Clinical Needs and Future Research.

Pulmonary and systemic insults from inhalation injury can complicate the care of burn patients and contribute to significant morbidity and mortality. However, recent progress in diagnosis and treatment of inhalation injury has not kept pace with the care of cutaneous thermal injury. There are many challenges unique to inhalation injury that have slowed advancement, including deficiencies in our understanding of its pathophysiology, the relative difficulty and subjectivity of bronchoscopic diagnosis, the lack of diagnostic biomarkers, the necessarily urgent manner in which decisions are made about intubation, and the lack of universal recommendations for the application of mucolytics, anticoagulants, bronchodilators, modified ventilator strategies, and other measures. This review represents a summary of critical shortcomings in our understanding and management of inhalation injury identified by the American Burn Association's working group on Cutaneous Thermal Injury and Inhalation Injury in 2018. It addresses our current understanding of the diagnosis, pathophysiology, and treatment of inhalation injury and highlights topics in need of additional research, including 1) airway repair mechanisms; 2) the airway microbiome in health and after injury; and 3) candidate biomarkers of inhalation injury.

Inhibition of Microsomal Prostaglandin E Synthase-1 in Cancer-Associated Fibroblasts Suppresses Neuroblastoma Tumor Growth

Despite recent progress in diagnosis and treatment, survival for children with high-risk metastatic neuroblastoma is still poor. Prostaglandin E2 (PGE2)-driven inflammation promotes tumor growth, immune suppression, angiogenesis and resistance to established cancer therapies. In neuroblastoma, cancer-associated fibroblasts (CAFs) residing in the tumor microenvironment are the primary source of PGE2. However, clinical targeting of PGE2 with current non-steroidal anti-inflammatory drugs or cyclooxygenase inhibitors has been limited due to risk of adverse side effects. By specifically targeting microsomal prostaglandin E synthase-1 (mPGES-1) activity with a small molecule inhibitor we could block CAF-derived PGE2 production leading to reduced tumor growth, impaired angiogenesis, inhibited CAF migration and infiltration, reduced tumor cell proliferation and a favorable shift in the M1/M2 macrophage ratio. In this study, we provide proof-of-principle of the benefits of targeting mPGES-1 in neuroblastoma, applicable to a wide variety of tumors. This non-toxic single drug treatment targeting infiltrating stromal cells opens up for combination treatment options with established cancer therapies.

The present and future role of ultrasound targeted microbubble destruction in preclinical studies of cardiac gene therapy.

Multiple limitations for cardiac pharmacologic therapies like intolerance, individual variation in effectiveness, side effects, and high cost still remain, despite the recent progress in diagnosis and health support. Gene therapy is poised to be an attractive alternative in various ways for the future, refractory cardiac diseases being one aspect of it. As a novel therapy to deliver the objective gene to organs of living animals, ultrasound targeted microbubble destruction (UTMD) has therapeutic potential in cardiovascular disorders. UTMD, which binds microbubbles with DNA or RNA carriers into the shell and destroys the located microbubbles with low frequency and high mechanical index ultrasound can release target agents to specific organs. UTMD has the ability to transfect markedly through sonoporation, cavitation and other effects by way of intravenous injection that is minimally invasive and highly specific for gene deliverance. Here, we have summarized the present role of UTMD in pre-clinical studies of cardiac gene therapy which covers myocardial infarction, regeneration, ischaemia/reperfusion injury, hypertension, diabetic cardiomyopathy, adriamycin cardiomyopathy and some discussion for further studies.

Prognostic Value of FBXO39 and ETS-1 but not BMI-1 in Iranian Colorectal Cancer Patients

Background:Colorectal cancer (CRC) is one of the most prevalent cancers worldwide. Despite recent progress in diagnosis and treatment, it remains a major health problem and further studies are needed. We here investigated expression profiles of the FBXO39, ETS-1 and BMI-1 genes in CRCs to validate any possible diagnostic/prognostic significance.Material and Methods:Thirty six patients with locally advanced CRC admitted to Hazrate-Rasoul Hospital-Tehran were enrolled. Initially the expression pattern of FBXO39, ETS-1 and BMI-1 genes were determined using RT-PCR in CRC tumor and adjacent normal tissues then real-time RT-PCR was employed to quantify BMI-1 gene expression.Results:FBXO39 expression was restricted to tumor tissues. Interestingly, expression of this gene was detected in all stage-0 tumor samples. There was a significant relation between FBXO39 gene expression and lymph node involvement. The ETS-1 gene was expressed in 66% of all tumor tissues with p-value=0.03 for increase as compared to the adjacent normal samples. In addition, there was a significant relation between ETS-1 gene expression and tumor size and lymph node involvement. RT-PCR demonstrated BMI-1 gene expression in both tumor and normal tissues and quantification by real-time RT-PCR showed no association between BMI-1 levels and CRC clinicopathological features.Conclusion:Expression of FBXO39 and ETS-1 with lymph node involvement may be considered as an alarm for the occurrence of CRC metastasis, and therfore have prognostic value while BMI-1 appears without importance.

Gravin and survivin gene expression levels as possible therapeutic targets for acute myeloid leukemia in adult Egyptian patients

Background Despite the recent progress in diagnosis and management, acute myeloid leukemia (AML) still remains a fatal hematologic malignancy, which invites the need for accurate predictors of clinical outcome. Objective The aim of the present study was to explore the possible prognostic importance of gravin and survivin gene expression in adult patients with de-novo AML by correlating their expression levels with response to induction therapy, disease-free survival (DFS), and overall survival (OS). Patients and methods This study was conducted on 105 patients with de-novo AML, and 45 age-matched and sex-matched patients were selected as a control group. RNA isolation from bone marrow aspirates or peripheral blood and cDNA preparation followed by quantitative real-time reverse transcription-PCR were done to assess expression of gravin and survivin. Results Gravin expression was markedly downregulated whereas survivin gene showed an overexpression in AML cases. There was a significant association between gravin and survivin expression levels with poor clinical outcome. OS and DFS were significantly lower in patients with low gravin and high survivin expression levels. Conclusion Survivin overexpression and gravin downregulation were significantly associated with adverse clinical outcome and tendency to chemoresistance in AML. The degree of their expression derangement has been found to be correlated with a lower complete remission rate and shorter OS and disease-DFS which renders them as future candidates for target through adjuvant immunotherapy.

Frontline treatment of AML in adults.

Despite recent progress in diagnosis and leukemogenesis based on genomic landscapes in acute myelogenous leukemia (AML), advances in AML treatment lag behind. Over the past four decades, combination chemotherapy with anthracycline and cytarabine remains the standard induction therapy. Subsequent post-remission consolidation therapy stratifies patients into favorable-risk, intermediate-risk, and unfavorable-risk groups to assign post-remission therapies based on cytogenetic abnormalities and molecular mutations. Allogeneic stem-cell transplant decreases the risk of AML recurrence compared to standard chemotherapy, but it also raises the risk of serious complications. Recent large collections of matched genomic and clinical data may assist in selecting the best individualized therapy for each AML patient. Emerging evidence indicates that molecularly targeted therapies such as FLT3 and IDH inhibitors may be effective in distinct AML subtypes, providing further rationale for a personalized medicine approach. An umbrella trial, such as "BEAT AML Master Trial," designed to offer novel targeted therapy to AML patients based on their genetic characteristics, will be launching worldwide in the near future.