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Abstract Background Catenin (Cadherin-Associated Protein), Beta 1 (CTNNB1) genomic alterations are rare in prostate cancer (PCa). Gain-of-function mutations lead to overexpression of β-catenin, with consequent hyperactivation of the Wnt/β-catenin signaling pathway, implicated in PCa progression and treatment resistance. To date, successful targeted treatment options for Wnt/β-catenin - driven PCa are lacking. Methods We report a rare histologic transformation of a CTNNB1 (β-catenin) mutated metastatic castration resistant prostate cancer (mCRPC), clinically characterized by highly aggressive disease course. We histologically and molecularly characterized the liver metastatic tumor samples, as well as successfully generated patient-derived organoids (PDOs) and patient-derived xenograft (PDX) from a liver metastasis. We used the generated cell models for further molecular characterization and drug response assays. Results Immunohistochemistry of liver metastatic biopsies and PDX tumor showed lack of expression of typical PCa (e.g., AR, PSA, PSAP, ERG) or neuroendocrine markers (synaptophysin), compatible with double-negative CRPC, but was positive for nuclear β-catenin expression, keratin 7 and 34βE12. ERG rearrangement was confirmed by fluorescent in situ hybridization (FISH). Drug response assays confirmed, in line with the clinical disease course, lack of sensitivity to common drugs used in mCRPC (e.g., enzalutamide, docetaxel). The casein kinase 1 (CK1) inhibitor IC261 and the tankyrase 1/2 inhibitor G700-LK showed modest activity. Moreover, despite harbouring a CTNNB1 mutation, PDOs were largely insensitive to SMARCA2/4- targeting PROTAC degraders and inhibitor. Conclusions The reported CTNNB1-mutated mCRPC case highlights the potential challenges of double-negative CRPC diagnosis and underlines the relevance of further translational research to enable successful targeted treatment of rare molecular subtypes of mCRPC.

Highlights To summarize the mechanisms and pathophysiological features of ALI after burn. To classify the targets for the treatment of ALI. Describe the types of nanomedicines used to treat ALI. These findings suggest the prospects and outlook for nanomaterial-targeted therapy for ALI.

Lung cancer has surpassed other types of cancer to become the primary cause of cancer-related deaths. Surgery stands as the foremost clinical treatment strategy available for tackling this condition, but it receives a low efficiency for most patients. In recent years, some adjuvant therapies are employed to improve the lung cancer treatment efficiency, such as chemotherapy, targeted therapy and immunotherapy. However, these strategies have not significantly increased overall survival of patients. Additionally, the random distribution of drugs will induce severe side effects. Nanomedicines have got great attentions to boost drug effect and reduce adverse reactions, including liposome-based nanoparticles, polymeric nanoparticles, inorganic nanoparticles, and exosomes. Importantly, nanomedicines contribute to improving drug bioavailability, stability and residency in target regions. Benefiting from the physiological characteristics of lung, the inhaled pulmonary delivery strategy in combination with nanomedicine will provide a non-invasive and effective strategy for treating lung cancer. Furthermore, the use of targeting ligands enables precise delivery of loaded drugs to lung cancer cells. Inhaled nanomedicine exhibits unique distribution and sustained release behaviors in the alveoli, amplifying the therapeutic effect and reducing side effects. This review aims to discuss various inhaled methods of delivering nanomedicine to treat lung cancer and also summarizes the clearance mechanism of nanomedicine in the lung. Overall, this review focuses on the application of different inhalable nanomedicines, which may inspire the development of more effective treatments against lung cancer.

Simple Summary: Isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) are essential metabolic enzymes involved in the tricarboxylic acid (TCA) cycle. Several mutations in IDH genes have recently been described in many solid tumors, including glioma, cholangiocarcinoma, and chondrosarcoma. These mutations lead to neomorphic enzymatic activity affecting cancer pathogenesis. This review aims to summarize the diagnostic and prognostic role of IDH mutations and to provide an overview of the actual IDH inhibitor-based therapies used in various solid malignancies, outlining the findings of the most recent clinical trials and searching for future perspectives. The isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) enzymes are involved in key metabolic processes in human cells, regulating differentiation, proliferation, and oxidative damage response. IDH mutations have been associated with tumor development and progression in various solid tumors such as glioma, cholangiocarcinoma, chondrosarcoma, and other tumor types and have become crucial markers in molecular classification and prognostic assessment. The intratumoral and serum levels of D-2-hydroxyglutarate (D-2-HG) could serve as diagnostic biomarkers for identifying IDH mutant (IDHmut) tumors. As a result, an increasing number of clinical trials are evaluating targeted treatments for IDH1/IDH2 mutations. Recent studies have shown that the focus of these new therapeutic strategies is not only the neomorphic activity of the IDHmut enzymes but also the epigenetic shift induced by IDH mutations and the potential role of combination treatments. Here, we provide an overview of the current knowledge about IDH mutations in solid tumors, with a particular focus on available IDH-targeted treatments and emerging results from clinical trials aiming to explore IDHmut tumor-specific features and to identify the clinical benefit of IDH-targeted therapies and their combination strategies. An insight into future perspectives and the emerging roles of circulating biomarkers and radiomic features is also included. [ABSTRACT FROM AUTHOR]

Unfortunately, ovarian cancer is still diagnosed most often only in an advanced stage and is also the most lethal gynecological cancer. Another problem is the fact that treated patients have a high risk of disease recurrence. Moreover, ovarian cancer is very diverse in terms of molecular, histological features and mutations. Many patients may also develop platinum resistance, resulting in poor response to subsequent lines of treatment. To improve the prognosis of patients with ovarian cancer, it is expected to make better existing and implement new, promising treatment methods. Targeted therapies seem very promising. Currently, bevacizumab - a VEGF inhibitor and therapy with olaparib - a polyADP-ribose polymerase inhibitor are approved. Other methods worth considering in the future include: folate receptor a, immune checkpoints or other immunotherapy methods. To improve the treatment of ovarian cancer, it is also important to ameliorate the determination of molecular features to describe and understand which group of patients will benefit most from a given treatment method. This is important because a larger group of patients treated for ovarian cancer can have a greater chance of surviving longer without recurrence. [ABSTRACT FROM AUTHOR]

Background: Catenin (Cadherin-Associated Protein), Beta 1 (CTNNB1) genomic alterations are rare in prostate cancer (PCa). Gain-of-function mutations lead to overexpression of β-catenin, with consequent hyperactivation of the Wnt/β-catenin signaling pathway, implicated in PCa progression and treatment resistance. To date, successful targeted treatment options for Wnt/β-catenin - driven PCa are lacking. Methods: We report a rare histologic transformation of a CTNNB1 (β-catenin) mutated metastatic castration resistant prostate cancer (mCRPC), clinically characterized by highly aggressive disease course. We histologically and molecularly characterized the liver metastatic tumor samples, as well as successfully generated patient-derived organoids (PDOs) and patient-derived xenograft (PDX) from a liver metastasis. We used the generated cell models for further molecular characterization and drug response assays. Results: Immunohistochemistry of liver metastatic biopsies and PDX tumor showed lack of expression of typical PCa (e.g., AR, PSA, PSAP, ERG) or neuroendocrine markers (synaptophysin), compatible with double-negative CRPC, but was positive for nuclear β-catenin expression, keratin 7 and 34βE12. ERG rearrangement was confirmed by fluorescent in situ hybridization (FISH). Drug response assays confirmed, in line with the clinical disease course, lack of sensitivity to common drugs used in mCRPC (e.g., enzalutamide, docetaxel). The casein kinase 1 (CK1) inhibitor IC261 and the tankyrase 1/2 inhibitor G700-LK showed modest activity. Moreover, despite harbouring a CTNNB1 mutation, PDOs were largely insensitive to SMARCA2/4- targeting PROTAC degraders and inhibitor. Conclusions: The reported CTNNB1-mutated mCRPC case highlights the potential challenges of double-negative CRPC diagnosis and underlines the relevance of further translational research to enable successful targeted treatment of rare molecular subtypes of mCRPC. [ABSTRACT FROM AUTHOR]

Highlights: To summarize the mechanisms and pathophysiological features of ALI after burn. To classify the targets for the treatment of ALI. Describe the types of nanomedicines used to treat ALI. These findings suggest the prospects and outlook for nanomaterial-targeted therapy for ALI. Acute lung injury (ALI) is a common complication in patients with severe burns and has a complex pathogenesis and high morbidity and mortality rates. A variety of drugs have been identified in the clinic for the treatment of ALI, but they have toxic side effects caused by easy degradation in the body and distribution throughout the body. In recent years, as the understanding of the mechanism underlying ALI has improved, scholars have developed a variety of new nanomaterials that can be safely and effectively targeted for the treatment of ALI. Most of these methods involve nanomaterials such as lipids, organic polymers, peptides, extracellular vesicles or cell membranes, inorganic nanoparticles and other nanomaterials, which are targeted to reach lung tissues to perform their functions through active targeting or passive targeting, a process that involves a variety of cells or organelles. In this review, first, the mechanisms and pathophysiological features of ALI occurrence after burn injury are reviewed, potential therapeutic targets for ALI are summarized, existing nanomaterials for the targeted treatment of ALI are classified, and possible problems and challenges of nanomaterials in the targeted treatment of ALI are discussed to provide a reference for the development of nanomaterials for the targeted treatment of ALI. [ABSTRACT FROM AUTHOR]

PurposeEndometrial cancer (EMCA) is the most common gynecologic malignancy, and new diagnoses are increasing in the United States. Black patients are more likely to present with advanced stage, be diagnosed with high-risk uterine serous carcinoma (USC) and die of their cancer.MethodsPatients with endometrial adenocarcinoma who received tumor FoundationOne CDx testing at our institution between January 2017 and August 2022 were identified. Genomic alterations, demographic and clinical characteristics were collected. Descriptive statistics and Fisher’s exact test were used to analyze data.ResultsA total of 289 patients (29.4% Black and 52.6% White) with advanced or recurrent endometrial adenocarcinoma underwent FoundationOne CDx testing. USC comprised 26.3% (76 of 289) of tested tumors. Of USC tumors, 33 of 76 (44%) were of Black race. USC occurred more frequently in Black patients (33 of 85 [38.8%] Black patients compared to 30 of 152 [19.7%] White patients, p

Glaucoma presents a significant global health concern and affects millions of individuals worldwide and predicted a high increase in prevalence of about 111 million by 2040. The current standard treatment involves hypotensive eye drops; however, challenges such as patient adherence and limited drug bioavailability hinder the treatment effectiveness. Nanopharmaceuticals or nanomedicines offer promising solutions to overcome these obstacles. In this manuscript, we summarized the current limitations of conventional antiglaucoma treatment, role of nanomedicine in glaucoma treatment, rational design, factors effecting the performance of nanomedicine and different types of nanocarriers in designing of nanomedicine along with their applications in glaucoma treatment from recent literature. Current clinical challenges that hinder real-time application of antiglaucoma nanomedicine are highlighted. Lastly, future directions are identified for improving the therapeutic potential and translation of antiglaucoma nanomedicine into clinic.

Simple Summary: Cholangiocarcinoma is a rare cancer with a dismal prognosis. The rate of recurrence after treatment of localized disease is high. In this review, we discuss the evidence regarding the use of radiation to improve outcomes in unresectable cholangiocarcinoma. We also discuss studies that have incorporated radiation before and after surgery. The review also briefly highlights recent developments in systemic therapy, especially targeted treatments and immunotherapy. Cholangiocarcinoma (CCA) is a rare cancer of bile ducts. It is associated with a poor prognosis. The incidence of CCA is rising worldwide. Anatomical subgroups have been used to classify patients for treatment and prognosis. There is a growing understanding of clinically important distinctions based on underlying genetic differences that lead to different treatment options and outcomes. Its management is further complicated by a heterogeneous population and relative rarity, which limits the conduct of large trials to guide management. Surgery has been the primary method of therapy for localized disease; however, recurrence and death remain high with or without surgery. Therefore, there have been concerted efforts to investigate new treatment options, such as the use of neoadjuvant treatments to optimize surgical outcomes, targeted therapy, leveraging a new understanding of immunobiology and stereotactic radiation. In this narrative review, we address the evidence to improve suboptimal outcomes in unresectable CCA with radiation, as well as the role of radiation in neoadjuvant and postoperative treatment. We also briefly discuss the recent developments in systemic treatment with targeted therapies and immune checkpoint inhibitors. [ABSTRACT FROM AUTHOR]

Clusterin (CLU) protein is involved in various pathophysiological processes including carcinogenesis and tumor progression. In recent years, the role of the secretory isoform has been demonstrated in tumor cells, where it inhibits apoptosis and favors the acquisition of resistance to conventional treatments used to treat cancer. To determine the possible therapeutic potential of inhibiting this protein, numerous studies have been carried out in this field. In this article, we present the existing knowledge to date on the inhibition of this protein in different types of cancer and analyze the importance it could have in the development of new therapies targeted against this disease. [ABSTRACT FROM AUTHOR]

New targeted treatments are urgently needed to improve triple-negative breast cancer (TNBC) patient survival. Previously, we identified the cell surface protein A Disintegrin And Metalloprotease 8 (ADAM8) as a driver of TNBC tumor growth and spread via its metalloproteinase and disintegrin (MP and DI) domains. In proof-of-concept studies, we demonstrated that a monoclonal antibody (mAb) that simultaneously inhibits both domains represents a promising therapeutic approach. Here, we screened a hybridoma library using a multistep selection strategy, including flow cytometry for Ab binding to native conformation protein and in vitro cell-based functional assays to isolate a novel panel of highly specific human ADAM8 dual MP and DI inhibitory mAbs, called ADPs. The screening of four top candidates for in vivo anti-cancer activity in an orthotopic MDA-MB-231 TNBC model of ADAM8-driven primary growth identified two lead mAbs, ADP2 and ADP13. Flow cytometry, hydrogen/deuterium exchange–mass spectrometry (HDX-MS) and alanine (ALA) scanning mutagenesis revealed that dual MP and DI inhibition was mediated via binding to the DI. Further testing in mice showed ADP2 and ADP13 reduce aggressive TNBC characteristics, including locoregional regrowth and metastasis, and improve survival, demonstrating strong therapeutic potential. The continued development of these mAbs into an ADAM8-targeted therapy could revolutionize TNBC treatment. [ABSTRACT FROM AUTHOR]

Aim: To explore the incorporation of novel agents in the first-line setting for acute myeloid leukemia patients. Materials & methods: Observational study based on data from a multi-country cross-sectional retrospective web-based survey sent to 518 physicians in Europe between 2020 and 2021. Information from 2040 patients was analyzed. Results: 604 patients (29.6%) received novel agents in both intensive and non-intensive setting. Comorbidities were not a barrier for the use of novel agents. The presence of tumor mutations was observed to be an important element for treatment decision. Conclusion: There is a progressive incorporation of novel agents for newly diagnosed acute myeloid leukemia patients. We now have new treatments for patients suffering from a type of blood cancer called acute myeloid leukemia (acronym AML). They are available as the first choice of therapy. In this study we explored how these new treatments are included in daily patient care. We reviewed the data of 2040 patients in Europe, obtained from an online survey sent to physicians in two waves (between 2020 and 2021). The use of these new AML treatments was more frequent in patients who presented some specific gene alterations (changes in their DNA sequence) and were in worse health due to other diseases and old age. Most of the new treatments were administered together with other milder chemotherapies. The results of this study help us understand how new AML treatments are being used. Observational study with 2040 AML patients showed incorporation of novel therapies into 1st line in combination with hypomethylating agents. Presence of tumor mutations observed to be an important element for treatment decision. [ABSTRACT FROM AUTHOR]

Background: The chloride intracellular channels (CLICs) family includes six ion channels (CLIC1-CLIC6) expressed on the cellular level and secreted into interstitial fluid and blood. They are involved in the physiological functioning of multiple systems as well as the pathogenetic processes of cancer. CLICs play essential roles in the tumor microenvironment. The current systematic review aimed at identifying and summarizing the research of CLICs in oncology on clinical material to assess CLICs' potential as novel biomarkers and personalized therapy targets. Materials and methods: The authors systematically searched the PubMed database for original articles concerning CLIC research on clinical material of all types of cancer -- fluids and tissues. Results: Fifty-three articles investigating in summary 3944 clinical samples were qualified for the current review. Studied material included 3438 tumor samples (87%), 437 blood samples (11%), and 69 interstitial fluid samples (2%). Studies investigated 21 cancer types, mostly hepatocellular carcinoma, colorectal, ovarian, and gastric cancer. Importantly, CLIC1, CLIC2, CLIC3, CLIC4, and CLIC5 were differently expressed in cancerous tissues and patients' blood compared to healthy controls. Moreover, CLICs were found to be involved in several cancer-associated signaling pathways, such as PI3K/AKT, MAPK/ERK, and MAPK/p38. Conclusion: CLIC family members may be candidates for potential novel cancer biomarkers due to the contrast in their expression between cancerous and healthy tissues and secretion to the interstitial fluid and blood. CLICs are investigated as potential therapeutic targets because of their involvement in cancer pathogenesis and tumor microenvironment. [ABSTRACT FROM AUTHOR]

Osteoarthritis (OA) of the temporomandibular joint (TMJ) occurs spontaneously in humans and various animal species, including horses. In humans, obtaining tissue samples is challenging and clinical symptoms appear late in the disease progression. Therefore, genetically modified, induced, and naturally occurring animal models play a crucial role in understanding the pathogenesis and evaluating potential therapeutic interventions for TMJ OA. Among the naturally occurring models, the equine TMJ OA model is characterized by slow, age-related progression, a wide range of clinical examinations, and imaging modalities that can be performed on horses, as well as easy tissue and synovial fluid collection. The morphological and functional similarities of TMJ structures in both species make the equine model of TMJ OA an excellent opportunity to track disease progression and response to treatment. However, much work remains to be carried out to determine the utility of human TMJ OA biomarkers in horses. Among the main TMJ OA biomarkers, IL-1, IL-6, TGF-β, TNF-α, and PGE2 have been recently investigated in the equine model. However, the majority of biomarkers for cartilage degradation, chondrocyte hypertrophy, angiogenesis, and TMJ overload—as well as any of the main signaling pathways—have not been studied so far. Therefore, it would be advisable to focus further research on equine specimens, considering both mediators and signaling. [ABSTRACT FROM AUTHOR]

Background and purpose: The Precision Oncology Platform (POP) trial represents the effort of the Portuguese Oncology Institute of Porto (IPO Porto) for joining other leading European institutions in both ‘Personalised Cancer Medicine for all EU citizens’ (PCM4EU), and ‘PRecisIon Cancer MEdicine RepurpOsing SystEm Using Pragmatic Clinical Trials’ (PRIME-ROSE) consortia, enabling the development of the Portuguese version of the Drug Rediscovery Protocol (DRUP)-like Clinical Trial (DLCT), based on the experience of the DRUP trial developed in The Netherlands. Patients/material and methods: The POP trial is a phase II, pragmatic multicentric, non-randomised, open-label study, designed entirely like the other DLCTs. Its primary objective is to describe anti-tumour activity of targeted anticancer drugs in patients with advanced malignancies harbouring actionable molecular alterations. The primary endpoint is disease control rate (DCR). Secondary endpoints encompass treatment-related grade ≥3 adverse events, objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), and overall survival (OS). Exploratory objectives will assess biomarkers, resource use and costs, and patient-reported outcome measures (PROMs). Interpretation: The POP trial will offer access to innovative treatments for patients without further therapeutic options and provide evidence on efficacy and safety of molecularly-guided treatments. Methodologically, it represents a pioneer approach in Portugal, including a pay-for-performance model embedded in the clinical trial. The POP trial represents a unique opportunity to integrate clinical research within cancer care, pursuing an evidence-based precision oncology strategy, and facilitating its rational and cost-effective implementation into the Portuguese healthcare system.

Unfortunately, ovarian cancer is still diagnosed most often only in an advanced stage and is also the most lethal gynecological cancer. Another problem is the fact that treated patients have a high risk of disease recurrence. Moreover, ovarian cancer is very diverse in terms of molecular, histological features and mutations. Many patients may also develop platinum resistance, resulting in poor response to subsequent lines of treatment. To improve the prognosis of patients with ovarian cancer, it is expected to make better existing and implement new, promising treatment methods. Targeted therapies seem very promising. Currently, bevacizumab - a VEGF inhibitor and therapy with olaparib - a polyADP-ribose polymerase inhibitor are approved. Other methods worth considering in the future include: folate receptor α, immune checkpoints or other immunotherapy methods. To improve the treatment of ovarian cancer, it is also important to ameliorate the determination of molecular features to describe and understand which group of patients will benefit most from a given treatment method. This is important because a larger group of patients treated for ovarian cancer can have a greater chance of surviving longer without recurrence.

Recent studies have shown that cross reacting material (CRM197), a nontoxic variant of diphtheria toxin, may play an important role in treating cancers with poor prognoses. Doxorubicin-hydrochloride (DOX) is an antineoplastic prescription medicine for the treatment of certain types of cancer. Considering that CRM197 is a known carrier in targeted delivery, CRM197-DOX complexes might be a step towards targeted therapy and reduced overall toxicity. Aim. This study aims to explore the potential to inhibit the growth of tumour cells. To achieve that goal, we evaluated the usage of CRM197-DOX complexes in squamous carcinoma cell line A431 and compared it with the effect on other immortalised cell lines. The methods used in this research include derivation and purification of recombinant CRM197 through immobilized-metal affinity chromatography and electrophoresis in a denaturing polyacrylamide gel. DOX-loaded CRM197 complexes were formed by the addition of a 5 μM solution of doxorubicin to 0.5 μg of protein with further dialysis in PBS. The cell viability assay was conducted using free CRM197 at different concentrations, DOX, CRM197 with DOX, as well as DOX-loaded CRM197. DOX-loaded CRM197 along with CRM197 with the addition of DOX showed significant differences in cell viability compared to control wells. CRM197- Results. DOX complexes have an evident inhibitory effect on epidermoid carcinoma cell growth and can be used as treatment against epithelial tumours, with CRM197 as a promising carrier for targeted drug delivery. Conclusions. CRM197-DOX complexes show evident inhibition of epidermoid carcinoma cell growth and can be used as treatment against epithelial tumours, especially those overexpressing the proHB-EGF and its receptors, EGFR1 and EGFR4, with CRM197 as a promising carrier for targeted drug delivery.

Rheumatoid arthritis （RA） is a systemic autoimmune disease characterized by chronic and erosive polyarthritis. The core pathological changes involve persistent synovial inflammation and angioproliferation，leading to the destruction of joint cartilage and bone. The etiology and pathogenesis of RA remain unclear and complex. Despite decades of accumulated evidence and experience in the treatment of RA，there are currently no definitive methods to reverse RA joint tissue damage. Nanoparticle drug delivery platforms，as systems based on nanomaterials for drug delivery，are designed to improve drug distribution，enhance therapeutic effects，and reduce drug-related toxic side effects. This review focuses on the pathogenesis of synovitis in RA and explores the application and potential of macrophage-targeted nanoparticle drug delivery platforms in the prevention and treatment of RA.

Introduction. Meningioma is one of the most common central nervous system tumors, accounting for 39.7 % of all primary brain tumors. The tumor originates from arachnoid meningothelial cells and is characterized by a wide range of histological types classified into 15 subtypes. The histological classification of meningiomas allows us to predict meningioma behavior and the risk of disease recurrence, as well as to define treatment strategies. However, clinical outcomes in histological subgroups of patients are often inconsistent with the histological grade of malignancy. Thus, a more reliable method is needed both to determine the histological subtype of the tumor and to predict the clinical course of the disease with the potential for targeted treatment.The purpose of the study was to summarize the available data on the effect of results of the genomic and proteomic tumor analysis on carcinogenesis with the relationship between the mutational changes and noninvasive diagnosis, treatment and the course of the disease.Material and Methods. Literature search was carried out in the PubMed, Elibrary system, publications were included mainly from 2010 to 2023. with the identification of articles by the keyword “genetic analysis of meningiomas” and synonyms. 550 articles were found, of which 55 were used to write a literature review.Conclusion. The study of the molecular genetic profile of meningiomas will improve the classification and establish a correlation with MRI data, the course of the disease and prognosis.

Reports of Ascaridia galli in laying hens in Europe have increased since the ban on conventional battery cages in 2012. As this parasite is transmitted directly via the faecal-oral route by parasite eggs containing a larva, it is reasonable to assume that the escalating problem is related to the increased exposure now occurring in modern welfare-friendly cage-free housing systems. On many farms, A. galli reappears in subsequent flocks, even though the birds have no access to the outdoors, biosecurity is high and empty houses are cleaned and disinfected during downtime. Since the egg production cycle lasts only ≈80 weeks and recombinant antigen production for helminth vaccines has not yet been solved, the development of a vaccine seems to be an unrealistic option. Therefore, disrupting the life cycle of the parasite by other means, including the strategic use of dewormers, appears to be the key to controlling infection. Of concern is that only one class of anthelmintics is licenced for poultry in Europe and that are usually administered indiscriminately through the birds' drinking water and often too late when the parasite is already established. If current calendar-based parasite control strategies are not changed, there is a risk that resistance to anthelmintics may develop, as has already been demonstrated with nematodes in livestock. We insist that treatments can be more effective and the risk of developing drug resistance can be mitigated if we invest in a better understanding of A. galli responses to more prudent and judicious use of anthelmintics. This review identifies knowledge gaps and highlights aspects of sustainable parasite control that require further research to support commercial egg producers.

Colorectal cancer (CRC) is a devastating disease that ranks third in diagnosis and as the second leading cause of cancer-related deaths. The early detection of CRC has been shown to be the most effective strategy to improve treatment outcomes and patient survival. Therefore, current lines of research focus on the development of reliable diagnostic tools. Targeted therapies, in combination with standard chemotherapy and immune checkpoint inhibitors, have emerged as promising treatment protocols in CRC. However, their effectiveness is linked to the molecular characteristics of each patient. The importance of discovering biomarkers that help predict response to therapies and assess prognosis is evident as they allow for a fundamental step towards personalized care and successful treatments. Among the ongoing efforts to identify them, mass spectrometry-based translational proteomics presents itself as a unique opportunity as it enables the discovery and application of protein biomarkers that may revolutionize the early detection and treatment of CRC. Our objective is to show the most recent studies focused on the identification of CRC-related protein markers, as well as to provide an updated view of advances in the field of proteomics and cancer. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic and erosive polyarthritis. The core pathological changes involve persistent synovial inflammation and angioproliferation, leading to the destruction of joint cartilage and bone. The etiology and pathogenesis of RA remain unclear and complex. Despite decades of accumulated evidence and experience in the treatment of RA, there are currently no definitive methods to reverse RA joint tissue damage. Nanoparticle drug delivery platforms, as systems based on nanomaterials for drug delivery, are designed to improve drug distribution, enhance therapeutic effects, and reduce drug-related toxic side effects. This review focuses on the pathogenesis of synovitis in RA and explores the application and potential of macrophage-targeted nanoparticle drug delivery platforms in the prevention and treatment of RA. [ABSTRACT FROM AUTHOR]

Reports of Ascaridia galli in laying hens in Europe have increased since the ban on conventional battery cages in 2012. As this parasite is transmitted directly via the faecal-oral route by parasite eggs containing a larva, it is reasonable to assume that the escalating problem is related to the increased exposure now occurring in modern welfare-friendly cage-free housing systems. On many farms, A. galli reappears in subsequent flocks, even though the birds have no access to the outdoors, biosecurity is high and empty houses are cleaned and disinfected during downtime. Since the egg production cycle lasts only ≈80 weeks and recombinant antigen production for helminth vaccines has not yet been solved, the development of a vaccine seems to be an unrealistic option. Therefore, disrupting the life cycle of the parasite by other means, including the strategic use of dewormers, appears to be the key to controlling infection. Of concern is that only one class of anthelmintics is licenced for poultry in Europe and that are usually administered indiscriminately through the birds' drinking water and often too late when the parasite is already established. If current calendar-based parasite control strategies are not changed, there is a risk that resistance to anthelmintics may develop, as has already been demonstrated with nematodes in livestock. We insist that treatments can be more effective and the risk of developing drug resistance can be mitigated if we invest in a better understanding of A. galli responses to more prudent and judicious use of anthelmintics. This review identifies knowledge gaps and highlights aspects of sustainable parasite control that require further research to support commercial egg producers. [Display omitted] • Research efforts to optimise the control of Ascaridia galli in laying hens are needed. • The use of a TT approach based on a combination of diagnostic tools is a viable control option. • Investigating the extent to which A. galli is resistant to BZ drugs should be a priority. • Advances in diagnostic parasitology offer the potential to fill knowledge gaps. • When and how to sample the flocks should not be ignored. [ABSTRACT FROM AUTHOR]

Background: In recent years, breast cancer has become the most common cancer in the world, increasing women's health risks. Approximately 60% of breast cancers are categorized as human epidermal growth factor receptor 2 (HER2)-low tumors. Recently, antibody-drug conjugates have been found to have positive anticancer efficacy in patients with HER2-low breast cancer, but more studies are required to comprehend their clinical and molecular characteristics. Methods: In this study, we retrospectively analyzed the data of 165 early breast cancer patients with pT1-2N1M0 who had undergone the RecurIndex testing. To better understand HER2-low tumors, we investigated the RecurIndex genomic profiles, clinicopathologic features, and survival outcomes of breast cancers according to HER2 status. Results: First, there were significantly more hormone receptor (HR)-positive tumors, luminal-type tumors, and low Ki67 levels in the HER2-low than in the HER2-zero. Second, RI-LR (P =.0294) and RI-DR (P =.001) scores for HER2-low and HER2-zero were statistically significant. Third, within HER2-negative disease, HR-positive/HER2-low tumors showed highest ESR1, NFATC2IP, PTI1, ERBB2, and OBSL1 expressions. Fourth, results of the survival analysis showed that lower expression of HER2 was associated with improved relapse-free survival for HR-positive tumors, but not for HR-negative tumors. Conclusions: The present study highlights the unique features of HER2-low tumors in terms of their clinical characteristics as well as their gene expression profiles. HR status may influence the prognosis of patients with HER2-low expression, and patients with HR-positive/HER2-low expression may have a favorable outcome. In this study, the data of patients with early stage breast cancer who had undergone RecurIndex testing was analyzed. To better understand HER2-low tumors, genomic profiles, clinicopathologic features, and survival outcomes of breast cancers according to HER2 status were investigated. [ABSTRACT FROM AUTHOR]

Tumoral heterogeneity has been associated with treatment resistance and failure in patients with cancer. Tumoral heterogeneity can be either intertumoral (static variation of cancer cells) or intratumoral (spatial and temporal variation of cancer cells). Nonsmall-cell lung cancer (NSCLC) is considered a model disease for the study of tumoral heterogeneity, given the emerging evidence about the clinical implications of genetic variations among NSCLC subtypes. This review provides an overview of the etiology, detection, and management methods of intratumoral heterogeneity in NSCLC and discusses their clinical implications.

Aim. To explore the potential to inhibit the growth of tumour cells which express EGF receptors, in this study, we evaluated the usage of CRM197-DOX complexes in squamous carcinoma cell line A431 and compared it with the effect on other immortalised cell lines such as 3T3 fibroblasts and kidney epithelial Vero cells. Methods. Cell lines. All cell lines were cultivated in a humidified 37 °C incubator with 5% CO2, using Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 10% heat-inactivated fetal bovine serum (FBS) and antibiotics. Protein extraction and purification. For recombinant CRM197 and HB-EGF protein expression, E.coli, containing pET28(a)-CRM197 and pET32(a)-HB-EGF plasmids respectively, were grown in the lysogeny broth with the edition of an antibiotic (Kanamycin or Ampicillin) for ~2 h at 37 °C. Later, each culture was induced with IPTG and was further grown for ~3 h at 30 °C. Both cultures were centrifuged, pellets resuspended in separate tubes with the buffer containing 6 M urea and lysed by ultrasound homogenisation. Homogenized cell mass was centrifuged and the supernatants containing CRM197 and HB-EGF were retained and used for the purification of respective proteins. PolyHis labelled CRM197 and HB-EGF were purified by Ni2+-NTA affinity chromatography and eluate fractions were dialysed in phosphate-buffered saline (PBS) [4]. Aliquots of proteins with sodium dodecyl sulfate (SDS) loading buffer were used for 10% SDS-PAGE. The gel was stained with Coomassie Brilliant Blue G-250. The expression of CRM197 and HB-EGF was confirmed by comparing bands appearing on the gel at ~58 kDa and ~10 kDa respectively. Complex loading. 5 μM of doxorubicin was dissolved in 1 ml of 20 mM Tris-HCl buffer. The DOX solution was added to the 0.5 μg of protein. Then, the heterogenous solution was mixed for 12 h at 4 °C with further dialysis in PBS (for loaded CRM197-DOX). MTT assay. Cells were cultivated in 96-well flat-bottomed plates in DMEM supplemented with 10% FBS and antibiotics for 24 h, then washed twice with PBS, and a fresh FBS-free culture medium was added. Control substances were added at the following concentrations: DOX — 5 μM, HB-EGF — 0.5 μg/ml, CRM197 — 0.5 μg/ml and 1 μg/ml, CRM197 + DOX — 0.5 μg/ml of protein and 5 μM of DOX, CRM197-DOX (loaded) — 0.5 μg/ml (according to protein). After incubation for 48 h in a humidified 37 °C incubator with 5% CO2, the optical density of the samples was measured using a multi-well spectrophotometer at 570 nm [5]. Statistics. Shapiro-Wilk test, one-way ANOVA and the Tukey–Kramer procedure were performed using Statistics Kingdom and showed significant effects for pairwise comparisons of control to test groups (P < 0.05). Results and Discussion. Analytic expression with further running SDS-PAGE (Fig. 1) indicated that CRM197 is extracted in an insoluble form; purified and eluated CRM197 (~0.1 mg/ml) in the fraction C was later used in the experiment (Fig. 2). In the A431 cell line (Fig. 3, A), treatment with CRM197 inhibited cell growth by 11% (0.5 μg/ ml) and 25% (1 μg/ml). CRM197 + DOX showed results similar to those of CRM197 at 1 μg/ml concentration and of 5 μM DOX. CRM197-DOX loaded complex inhibited cell growth by 17%. It is worth noting that the excess of unbound DOX was removed by dialysis, therefore the main cytostatic effect is caused by the loaded CRM197-DOX, adding to the hypothesis that these complexes may further be used for targeted treatment of tumour cells. The 3T3 cell line (Fig. 3, B) showed little to no reaction to CRM197 treatment but was excessively responding to treatment with doxorubicin-hydrochloride. CRM197 + DOX and the loaded CRM197- DOX showed results of 43% and 19% respectively. The Vero cell line (Fig. 3, C) reacted to CRM197 at 0.5 μg/ml with a growth inhibition by 26%, and both 1 μg/ml concentration and CRM197 + DOX showed a result of ~37%. The loaded complex showed efficiency of 31%. All CRM197 treatments were significantly more effective than DOX. Conclusions. CRM197-DOX complexes show evident inhibition of epidermoid carcinoma cell growth and can be used as treatment against epithelial tumours, especially those overexpressing the proHB-EGF and its receptors, EGFR1 and EGFR4, with CRM197 as a promising carrier for targeted drug delivery. Since DOX-loaded CRM197 complex shows lesser cytotoxicity than free DOX, we concluded that a certain amount of the antibiotic is lost in the process of loading, but DOX-loaded CRM197 complex still inhibits cell proliferation more strongly than free CRM197. However, there is still a need for more efficient loading techniques and to fill the gap of DOX to CRM197 loading process mechanisms. [ABSTRACT FROM AUTHOR]

Chronic consequences of mild traumatic brain injury (mTBI) are heterogeneous, but may be treatable with targeted medical and rehabilitation interventions. A biological signature for the likelihood of response to therapy (i.e., ?predictive? biomarkers) would empower personalized medicine post-mTBI. The purpose of this study was to correlate pre-intervention blood biomarker levels and the likelihood of response to targeted interventions for patients with chronic issues attributable to mTBI. Patients with chronic symptoms and/or disorders secondary to mTBI >3 months previous (104 days to 15 years; n?=?74) were enrolled. Participants completed pre-intervention assessments of symptom burden, comprehensive clinical evaluation, and blood-based biomarker measurements. Multi-domain targeted interventions for specific symptoms and impairments across a 6-month treatment period were prescribed. Participants completed a follow-up testing after the treatment period. An all-possible model's backward logistic regression was built to identify predictors of improvement in relation to blood biomarker levels before intervention. The minimum clinically important difference (MCID) of the change score (post-intervention subtracted from pre-intervention) for the Post-Concussion Symptom Scale (PCSS) to identify treatment responders from non-responders was the primary outcome. The MCID for total PCSS score was 10. The model to predict change in PCSS score over the 6-month intervention was significant (R2?=?0.09; p?=?0.01) and identified ubiquitin C-terminal hydrolase L1 (odds ratio [OR]?=?2.53; 95% confidence interval [CI], 1.18?5.46; p?=?0.02) and hyperphosphorylated tau (p-tau; OR?=?0.70; 95% CI, 0.51?0.96; p?=?0.03) as significant predictors of symptom improvement beyond the PCSS MCID. In this cohort of chronic TBI subjects, blood biomarkers before rehabilitation intervention predicted the likelihood of response to targeted therapy for chronic disorders post-TBI.

The management of wounds is a critical aspect of healthcare as it affects patients' quality of life and puts a financial burden on the healthcare industry. The development of smart bandages has shown great potential in wound monitoring and targeted treatment. This review paper gives information on the latest updates in smart bandage technology that can monitor various biomarkers such as temperature, moisture, oxygen, blood flow, external pressure, pH, and infection status in real time. Additionally, this review discusses targeted treatment by integrating drug delivery systems that can release drugs on-demand based on the wound condition. Furthermore, this paper gives a summary of information on the current improvements in smart bandages, including their design, fabrication, and clinical applications. This paper also discussed the current challenges and future opportunities with smart bandages and their potential to transform the field of wound care. With the ability to noninvasively diagnose wound parameters, reduce pain, and accelerate wound healing, smart bandages are expected to play a significant role in future wound care.

Drug resistance is a bottleneck in cancer treatment. Commonly, a molecular treatment for cancer leads to the emergence of drug resistance in the long term. Thus, some drugs, despite their initial excellent response, are withdrawn from the market. Lung cancer is one of the most mutated cancers, leading to dozens of targeted therapeutics available against it. Here, we have developed a mechanistic mathematical model describing sensitization to nine groups of targeted therapeutics and the emergence of intrinsic drug resistance. As we focus only on intrinsic drug resistance, we perform the computer simulations of the model only until clinical diagnosis. We have utilized, for model calibration, the whole-exome sequencing data combined with clinical information from over 1000 non-small-cell lung cancer patients. Next, the model has been applied to find an answer to the following questions: When does intrinsic drug resistance emerge? And how long does it take for early-stage lung cancer to grow to an advanced stage? The results show that drug resistance is inevitable at diagnosis but not always detectable and that the time interval between early and advanced-stage tumors depends on the selection advantage of cancer cells. [ABSTRACT FROM AUTHOR]

Colorectal cancer is the third most diagnosed cancer, behind only breast and lung cancer. In terms of overall mortality, it ranks second due to, among other factors, problems with screening programs, which means that one of the factors that directly impacts survival and treatment success is early detection of the disease. Clusterin (CLU) is a molecular chaperone that has been linked to tumorigenesis, cancer progression and resistance to anticancer treatments, which has made it a promising drug target. However, it is still necessary to continue this line of research and to adjust the situations in which its use is more favorable. The aim of this paper is to review the current genetic knowledge on the role of CLU in tumorigenesis and cancer progression in general, and discuss its possible use as a therapeutic target in colorectal cancer. [ABSTRACT FROM AUTHOR]

Nonprogrammed cell death (NPCD) and programmed cell death (PCD) are two types of cell death. Cell death is significantly linked to tumor development, medication resistance, cancer recurrence, and metastatic dissemination. Therefore, a comprehensive understanding of cell death is essential for the treatment of cancer. Pyroptosis is a kind of PCD distinct from autophagy and apoptosis in terms of the structure and function of cells. The defining features of pyroptosis include the release of an inflammatory cascade reaction and the expulsion of lysosomes, inflammatory mediators, and other cellular substances from within the cell. Additionally, it displays variations in osmotic pressure both within and outside the cell. Pyroptosis, as evidenced by a growing body of research, is critical for controlling the development of inflammatory diseases and cancer. In this paper, we reviewed the current level of knowledge on the mechanism of pyroptosis and inflammasomes and their connection to cancer and inflammatory diseases. This article presents a theoretical framework for investigating the potential of therapeutic targets in cancer and inflammatory diseases, overcoming medication resistance, establishing nanomedicines associated with pyroptosis, and developing risk prediction models in refractory cancer. Given the link between pyroptosis and the emergence of cancer and inflammatory diseases, pyroptosis‐targeted treatments may be a cutting‐edge treatment strategy. [ABSTRACT FROM AUTHOR]

Simple Summary: The purpose of our study was to examine remaining controversies in key issues about the treatment of GCTB. To achieve that we analysed a cohort of 102 patients treated in our institution between 2006 and 2020. We identified the main risk factors for local recurrence, evaluated the recurrence-free survival in dependence on neoadjuvant denosumab use and the type of procedure, and compared the functional outcomes after curettage and en bloc resection. Giant cell tumour of bone (GCTB) is one of the most common local aggressive tumourous lesions with a wide variety of biological behaviour. However, there are no clear indicative criteria when choosing the type of procedure and the complication rates remain high, especially in terms of local recurrence. The purpose of the study was to (1) identify the main risk factors for local recurrence, (2) evaluate the recurrence-free survival in dependence on neoadjuvant denosumab use and the type of procedure, and (3) compare the functional outcomes after curettage and en bloc resection. The group included 102 patients with GCTB treated between 2006 and 2020. The mean age of patients was 34.4 years (15–79). The follow-up period was 8.32 years (2–16) on average. Local recurrence occurred in 14 patients (29.8%) who underwent curettage and in 5 patients (10.6%) after en bloc resection. Curettage was shown to be a factor in increasing recurrence rates (OR = 3.64 [95% CI: 1.19–11.15]; p = 0.023). Tibial location was an independent risk factor for local recurrence regardless of the type of surgery (OR = 3.22 [95% CI: 1.09–9.48]; p = 0.026). The recurrence-free survival rate of patients treated with resection and denosumab was higher compared to other treatments at five years postoperatively (p = 0.0307). Functional ability and pain as reported by patients at the latest follow-up were superior after curettage compared to resection for upper and lower extremity (mean difference: −4.00 [95% CI: –6.81 to −1.18]; p < 0.001 and mean difference: −5.36 [95% CI: −3.74 to −6.97]; p < 0.001, respectively). Proximal tibia tumour location and curettage were shown to be major risk factors for local recurrence in GCTB regardless of neoadjuvant denosumab treatment. The recurrence-free survival rate of patients treated with resection and denosumab was higher compared to other treatments. The functional outcome of patients after curettage was better compared to en bloc resection. [ABSTRACT FROM AUTHOR]

Leptin receptor (LEPR) deficiency is a rare genetic disorder that affects the body's ability to regulate appetite and weight. For patients and their families, the disorder seriously disrupts daily life; however, little is published about this impact. We here report the experiences of a 10.5-year-old girl with leptin receptor deficiency and her family. The diagnosis of this rare genetic obesity had a deep impact on the life of the child and her family. It led to a better understanding of the cause of the impaired appetite regulation and early-onset obesity with subsequently less judgement by others and improved cooperation of their social network and school on maintaining a healthy lifestyle for this girl. A strict eating regimen and lifestyle measures resulted in the first year after diagnosis in a significantly decreased body mass index (BMI), followed by BMI stabilization, still categorized as obesity class three. However, the troublesome challenge of how to manage the disruptive behaviour due to hyperphagia remained. Eventually, due to treatment with targeted pharmacotherapy, i.e., melanocortin-4 receptor agonists, her BMI continued to decrease due to resolving hyperphagia. The daily routine of the family and the atmosphere at home positively changed as they were no longer dominated by the food-focused behaviour of the child and the adherence to the strict eating regimen. This case report demonstrates the importance and impact of a rare genetic obesity disorder diagnosis in a family. Additionally, it highlights the value of genetic testing in patients with a high suspicion of a genetic obesity disorder as it can eventually lead to personalized treatment, such as guidance by specialized healthcare professionals and educated caregivers or targeted pharmacotherapy. [ABSTRACT FROM AUTHOR]

Nathan Chanhanga,1 Tafadzwa Mindu,1 John Mogaka,1 Moses Chimbari1,2 1School of Nursing and Public Health, University of KwaZulu Natal, Durban, South Africa; 2Research and Innovation, Great Zimbabwe University, Masvingo, ZimbabweCorrespondence: Tafadzwa Mindu, Email mindutafadzwa@gmail.comAbstract: Schistosomiasis is a public health problem in more than 78 countries in the world. The disease is most prevalent among children than adults due to their high exposure to infectious water sources. Various interventions such as mass drug administration (MDA), snail control, safe water provision and health education have been implemented independently or jointly to control, reduce and ultimately eliminate Schistosomiasis. This scoping review focused on studies reporting the impact of different delivery strategies of targeted treatment and MDA on the prevalence and intensity of schistosomiasis infection in school aged children in Africa. The review focused on Schistosoma haematobium and Schistosoma mansoni species. A systematic search for eligible literature from peer-reviewed articles was done from Google Scholar, Medline, PubMed and EBSCO host databases. The search yielded twenty-seven peer-reviewed articles. All articles found reported a decrease in the prevalence of schistosomiasis infection. Five studies (18.5%) reported a prevalence change below 40%, eighteen studies (66.7%) reported a change between 40% and 80%, and four studies (14.8%) reported a change above 80%. The infection intensity post-treatment was varied: twenty-four studies reported a decrease, while two studies reported an increase. The review showed that the impact of targeted treatment on the prevalence and intensity of schistosomiasis depended on the frequency at which it was offered, complementary interventions, and its uptake by the target population. Targeted treatment can significantly control the infection burden, but cannot eliminate the disease. Constant MDA programs coupled with preventative and health promotional programs are required to reach the elimination stage.Keywords: schistosomiasis, mass drug administration, prevalence, intensity, targeted treatment, impact, school aged children

Background and objective Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) is the first choice for first-line treatment of advanced patients with EGFR positive non-small cell lung cancer (NSCLC). For advanced NSCLC patients with negative drive gene and positive programmed cell death ligand 1 (PD-L1) or highly expressed NSCLC patients, the first-line treatment recommends immune checkpoint inhibitors (ICIs) monotherapy or ICIs combined chemotherapy. Therefore, the first-line treatment strategy for advanced NSCLC patients with EGFR positive at different PD-L1 expression levels is worth further exploring. Many previous studies have suggested that the expression of PD-L1 is obviously affected by EGFR mutation, and the expression of PD-L1 is likely to be related to the mechanism of EGFR-TKIs resistance. The purpose of this study was to analyze the expression characteristics of PD-L1 in patients with advanced EGFR positive NSCLC and its relationship with the efficacy of EGFR-TKIs. Methods 159 patients with newly diagnosed advanced NSCLC with EGFR positive (including 141 patients with EGFR sensitive mutations) were enrolled to analyze the relationship between clinicopathological characteristics and PD-L1 expression. The factors affecting the therapeutic effect of EGFR-TKIs in 141 patients with EGFR sensitive mutations were also explored. Results The PD-L1 expression of the included patients was classified according to the tumor promotion score (TPS): negative (TPS

Clusterin (CLU) protein is involved in various pathophysiological processes including carcinogenesis and tumor progression. In recent years, the role of the secretory isoform has been demonstrated in tumor cells, where it inhibits apoptosis and favors the acquisition of resistance to conventional treatments used to treat cancer. To determine the possible therapeutic potential of inhibiting this protein, numerous studies have been carried out in this field. In this article, we present the existing knowledge to date on the inhibition of this protein in different types of cancer and analyze the importance it could have in the development of new therapies targeted against this disease.

New targeted treatments are urgently needed to improve triple-negative breast cancer (TNBC) patient survival. Previously, we identified the cell surface protein A Disintegrin And Metalloprotease 8 (ADAM8) as a driver of TNBC tumor growth and spread via its metalloproteinase and disintegrin (MP and DI) domains. In proof-of-concept studies, we demonstrated that a monoclonal antibody (mAb) that simultaneously inhibits both domains represents a promising therapeutic approach. Here, we screened a hybridoma library using a multistep selection strategy, including flow cytometry for Ab binding to native conformation protein and in vitro cell-based functional assays to isolate a novel panel of highly specific human ADAM8 dual MP and DI inhibitory mAbs, called ADPs. The screening of four top candidates for in vivo anti-cancer activity in an orthotopic MDA-MB-231 TNBC model of ADAM8-driven primary growth identified two lead mAbs, ADP2 and ADP13. Flow cytometry, hydrogen/deuterium exchange–mass spectrometry (HDX-MS) and alanine (ALA) scanning mutagenesis revealed that dual MP and DI inhibition was mediated via binding to the DI. Further testing in mice showed ADP2 and ADP13 reduce aggressive TNBC characteristics, including locoregional regrowth and metastasis, and improve survival, demonstrating strong therapeutic potential. The continued development of these mAbs into an ADAM8-targeted therapy could revolutionize TNBC treatment.

Abstract Nonprogrammed cell death (NPCD) and programmed cell death (PCD) are two types of cell death. Cell death is significantly linked to tumor development, medication resistance, cancer recurrence, and metastatic dissemination. Therefore, a comprehensive understanding of cell death is essential for the treatment of cancer. Pyroptosis is a kind of PCD distinct from autophagy and apoptosis in terms of the structure and function of cells. The defining features of pyroptosis include the release of an inflammatory cascade reaction and the expulsion of lysosomes, inflammatory mediators, and other cellular substances from within the cell. Additionally, it displays variations in osmotic pressure both within and outside the cell. Pyroptosis, as evidenced by a growing body of research, is critical for controlling the development of inflammatory diseases and cancer. In this paper, we reviewed the current level of knowledge on the mechanism of pyroptosis and inflammasomes and their connection to cancer and inflammatory diseases. This article presents a theoretical framework for investigating the potential of therapeutic targets in cancer and inflammatory diseases, overcoming medication resistance, establishing nanomedicines associated with pyroptosis, and developing risk prediction models in refractory cancer. Given the link between pyroptosis and the emergence of cancer and inflammatory diseases, pyroptosis‐targeted treatments may be a cutting‐edge treatment strategy.

Simple Summary: Dedifferentiated chondrosarcoma is a rare type of cancer that is very aggressive and has a poor prognosis with poor survival rates. This disease can affect anyone of any age, but it is usually diagnosed among people 50 years of age or older. There is no standard treatment available; usually it is based on surgery, however most patients are diagnosed with an advanced stage when radical treatment is not possible. We present the most up–to–date data on genetics, diagnostic procedures, and treatment options for localised and advanced diseases. Dedifferentiated chondrosarcoma (DDCS) is a rare subtype of chondrosarcoma, a primary cartilaginous malignant neoplasm. It accounts for up to 1–2% of all chondrosarcomas and is generally associated with one of the poorest prognoses among all chondrosarcomas with the highest risk of metastasis. The 5-year survival rates range from 7% to 24%. DDCS may develop at any age, but the average presentation age is over 50. The most common locations are the femur, pelvis humerus, scapula, rib, and tibia. The standard treatment for localised disease is surgical resection. Most patients are diagnosed in unresectable and advanced stages, and chemotherapy for localised and metastatic dedifferentiated DDCS follows protocols used for osteosarcoma. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) contains cancer stem cells (CSC) that are resistant to treatment. GBM CSC expresses glycolipids recognized by the A2B5 antibody. A2B5, induced by the enzyme ST8 alpha-N-acetyl-neuraminide alpha-2,8-sialyl transferase 3 (ST8Sia3), plays a crucial role in the proliferation, migration, clonogenicity and tumorigenesis of GBM CSC. Our aim was to characterize the resulting effects of neuraminidase that removes A2B5 in order to target GBM CSC. To this end, we set up a GBM organotypic slice model; quantified A2B5 expression by flow cytometry in U87-MG, U87-ST8Sia3 and GBM CSC lines, treated or not by neuraminidase; performed RNAseq and DNA methylation profiling; and analyzed the ganglioside expression by liquid chromatography–mass spectrometry in these cell lines, treated or not with neuraminidase. Results demonstrated that neuraminidase decreased A2B5 expression, tumor size and regrowth after surgical removal in the organotypic slice model but did not induce a distinct transcriptomic or epigenetic signature in GBM CSC lines. RNAseq analysis revealed that OLIG2, CHI3L1, TIMP3, TNFAIP2, and TNFAIP6 transcripts were significantly overexpressed in U87-ST8Sia3 compared to U87-MG. RT-qPCR confirmed these results and demonstrated that neuraminidase decreased gene expression in GBM CSC lines. Moreover, neuraminidase drastically reduced ganglioside expression in GBM CSC lines. Neuraminidase, by its pleiotropic action, is an attractive local treatment against GBM. [ABSTRACT FROM AUTHOR]

In recent years, poly (ADP-ribose) polymerase (PARP) inhibition has become a promising therapeutic option for several tumors, especially for those harboring a BRCA 1– 2 mutation or a deficit in the homologous recombination repair (HRR) pathway. Nevertheless, to date, PARP inhibitors are still not largely used for thoracic malignancies neither as a single agent nor in combination with other treatments. Recently, a deeper understanding of HRR mechanisms, alongside the development of new targeted and immunotherapy agents, particularly against HRR-deficient tumors, traced the path to new treatment strategies for many tumor types including lung cancer and malignant pleural mesothelioma. The aim of this review is to sum up the current knowledge about cancer-DNA damage response pathways inhibition and to update the status of recent clinical trials investigating the use of PARP inhibitors, either as monotherapy or in combination with other agents for the treatment of thoracic malignancies. We will also briefly discuss available evidence on Poly(ADP-Ribose) Glycohydrolase (PARG) inhibitors, a novel promising therapeutic option in oncology. [ABSTRACT FROM AUTHOR]

Galanin is a 30 amino acid peptide that stimulates three subtype receptors (GAL1–3R). M89b is a lanthionine-stabilized, C-terminally truncated galanin analog that specifically stimulates GAL2R. We investigated the potential of M89b as a therapeutic for pancreatic ductal adenocarcinoma (PDAC) and assessed its safety. The anti-tumor activity of subcutaneously injected M89b on the growth of patient-derived xenografts of PDAC (PDAC–PDX) in mice was investigated. In addition, the safety of M89b was assessed in vitro using a multi-target panel to measure the off-target binding and modulation of enzyme activities. In a PDAC–PDX with a high GAL2R expression, M89b completely inhibited the growth of the tumor (p < 0.001), while in two PDAC–PDXs with low GAL2R expression, low or negligeable inhibition of tumor growth was measured, and in the PDX without GAL2R expression no influence on the tumor growth was observed. The M89b treatment of the GAL2R high-PDAC–PDX-bearing mice led to a reduction in the expression of RacGap1 (p < 0.05), PCNA (p < 0.01), and MMP13 (p < 0.05). In vitro studies involving a multi-target panel of pharmacologically relevant targets revealedexcellent safety of M89b. Our data indicated that GAL2R is a safe and valuable target for treating PDACs with high GAL2R expression. [ABSTRACT FROM AUTHOR]

Introduction Cancer of unknown primary remains a challenging clinical entity. Despite receiving empiric chemotherapy, median overall survival is approximately 6-12 months. Site-specific therapy based on molecular characterization has been shown to improve outcomes; however, feasibility outside of clinical trials, especially in community centers, is lacking. This study explores the application of rapid next-generation sequencing in defining cancer of unknown primary and to identify therapeutic biomarkers. Methods A retrospective chart review was performed by identifying pathological samples designated cancer of unknown primary. Next-generation sequencing testing was based on an automated workflow utilizing the Genexus integrated sequencer, validated for clinical use. Genomic profiling was further integrated within a routine immunohistochemistry service, with results reported directly by anatomic pathologists. Results Between October 2020 and October 2021, 578 solid tumor samples underwent genomic profiling. Among this cohort, 40 were selected based on an initial diagnosis of cancer of unknown primary. The median (range) age at diagnosis was 70 (42-85) and 23 (57%) were female. Genomic data were used to support a site-specific diagnosis in 6 patients (15%). Median turnaround time was 3 business days (IQR: 1-5). Most common alterations identified were KRAS (35%), CDKN2A (15%), TP53 (15%), and ERBB2 (12%). Actionable molecular targeted therapies were identified in 23 (57%) patients, including alterations in BRAF, CDKN2A, ERBB2, FGFR2, IDH1 , and KRAS. Immunotherapy-sensitizing mismatch repair deficiency was identified in 1 patient. Conclusion This study supports the adoption of rapid next-generation sequencing among patients with cancer of unknown primary. We also demonstrate the feasibility of integration of genomic profiling with diagnostic histopathology and immunohistochemistry in a community practice setting. Diagnostic algorithms incorporating genomic profiling to better define cancer of unknown primary should be considered for future study. [ABSTRACT FROM AUTHOR]

Given significant genetic, molecular, and phenotypic overlaps, researchers have begun to investigate whether targeted treatments for Fragile X Syndrome (FXS) could also be beneficial for patients with Autism Spectrum Disorder (ASD). For example, low-dose sertraline, an SSRI, was used in two recent controlled trials in children with FXS and ASD. The first trial recruited 52 children with FXS, 32 of which were also diagnosed with ASD; the second trial recruited 58 children with non-syndromic ASD. One focus of the present study is to compare the response to sertraline between the FXS-associated ASD and non-syndromic ASD groups. Another focus is to compare baseline ASD-related characteristics between the groups and review these differences within the context of recent literature comparing these populations. Our comparison showed more severe ASD profiles in children with non-syndromic ASD vs. FXS-associated ASD. Regarding response to sertraline, the FXS-ASD group displayed significant improvements in language development, while the non-syndromic group did not show any significant improvements. One possible explanation for this differential response is the distinct anxiety profiles that are seen in these two groups. The heightened anxiety phenotype seen in those with FXS-ASD may have led to a greater relief of anxiety symptoms with sertraline compared to those with non-syndromic ASD; this, in turn, could have led to measurably greater developmental gains. Further research is required to solidify this connection between anxiety relief and developmental gains in these populations.

Triple-negative breast cancer (TNBC) is an aggressive subset of breast carcinomas that lack expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2). Unlike other breast cancer subtypes, targeted therapy is presently unavailable for patients with TNBC. In spite of initial responses to chemotherapy, drug resistance tends to develop rapidly and the prognosis of metastatic TNBC is poor. Hence, there is an urgent need for novel-targeted treatment methods or development of safe and effective alternatives with recognized mechanism(s) of action. AMP-activated protein kinase (AMPK), an energy sensor, can regulate protein and lipid metabolism responding to alterations in energy supply. In the past 10 years, interest in AMPK has increased widely since it appeared as an attractive targeting molecule for cancer therapy. There has been a deep understanding of the possible role of abnormal AMPK signaling pathways in the regulation of growth and survival and the development of drug resistance in TNBC. The increasing popularity of using AMPK regulators for TNBC-targeted therapy is supported by a considerable development in ascertaining the molecular pathways implicated. This review highlights the available evidence for AMPK-targeted anti-TNBC activity of various agents or treatment strategies, with special attention placed on recent preclinical and clinical advances in the manipulation of AMPK in TNBC. The elaborative analysis of these AMPK-related signaling pathways will have a noteworthy impact on the development of AMPK regulators, resulting in efficacious treatments for this lethal disease.

Background: Soft-tissue sarcoma (STS) is a heterogeneous group of sarcomas with a low incidence. The treatment of advanced disease is poor, and mortality is high. We aimed to generate an overview of the clinical experiences with targeted treatments based on a pre-specified target in patients with STS. Methods: A systematic literature search was conducted in PubMed and Embase databases. The programs ENDNOTE and COVIDENCE were used for data management. The literature was screened to assess the article's eligibility for inclusion. Results: Twenty-eight targeted agents were used to treat 80 patients with advanced STS and a known pre-specified genetic alteration. MDM2 inhibitors were the most-studied drug (n = 19), followed by crizotinib (n = 9), ceritinib (n = 8), and 90Y-OTSA (n = 8). All patients treated with the MDM2 inhibitor achieved a treatment response of stable disease (SD) or better with a treatment duration of 4 to 83 months. For the remaining drugs, a more mixed response was observed. The evidence is low because most studies were case reports or cohort studies, where only a few STS patients were included. Conclusions: Many targeted agents can precisely target specific genetic alterations in advanced STS. The MDM2 inhibitor has shown promising results. [ABSTRACT FROM AUTHOR]