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Introduction: Nasopharyngeal carcinoma (NPC) remains an endemic disease in certain parts of the world, with many patients presenting with advanced disease on diagnosis. Chemotherapy had remained the standard of care with minimal progress made until recent years. This review aims to provide an overview of recent significant breakthroughs and up-and-coming novel strategies in treating this deadly disease., Areas Covered: This review focuses on the latest clinical development of promising investigational agents in the treatment of advanced NPC. These include anti-vascular agents, signaling pathways inhibitors and immunotherapy., Expert Opinion: The addition of immune-checkpoint inhibitors (CPI) to platinum-based chemotherapy has undoubtedly changed the therapeutic landscape of R/M NPC in the first-line setting. This leaves much room for further research on the optimal treatment strategy in subsequent-line settings, likely including the addition of CPI to anti-vascular agents or novel CPI combinations, with or without chemotherapy as a backbone. Other potential approaches include optimal CPI maintenance therapy after first-line CPI-chemotherapy combination. Potential novel agents on the horizons are antibody-drug conjugates, bi-specific antibodies and signaling inhibitors, with several phase II/III studies currently underway.

Emerging evidence indicates that metabolism not only is a source of energy and biomaterials for cell division but also acts as a driver of cancer cell plasticity and treatment resistance. This is because metabolic changes lead to remodeling of chromatin and reprogramming of gene expression patterns, furthering tumor cell phenotypic transitions. Therefore, the crosstalk between metabolism and epigenetics seems to hold immense potential for the discovery of novel therapeutic targets for various aggressive tumors. Here, we highlight recent discoveries supporting the concept that the cooperation between metabolism and epigenetics enables cancer to overcome mounting treatment-induced pressures. We discuss how specific metabolites contribute to cancer cell resilience and provide perspective on how simultaneously targeting these key forces could produce synergistic therapeutic effects to improve treatment outcomes., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The COVID-19 pandemic demonstrated that the current purely market-driven approaches to drug discovery and development alone are insufficient to drive equitable access to new therapies either in preparation for, or in response to, pandemics. A new global framework driven by equity is under negotiation at the World Health Organization to support pandemic preparedness and response. Some believe that the global intellectual property (IP) system itself is part of the problem and propose a purely Open Science approach. In this article, we discuss how existing IP frameworks and contractual agreements may be used to create rights and obligations to generate a more effective global response in future, drawing on experience gained in the COVID Moonshot program, a purely Open Science collaboration, and the ASAP AViDD drug discovery consortium, which uses a hybrid, phased model of Open Science, patent filing and contractual agreements. We conclude that 'straight to generic' drug discovery is appropriate in some domains, and that targeted patent protection, coupled with open licensing, can offer a route to generating affordable and equitable access for therapy areas where market forces have failed. The Extended Data contains a copy of our model IP policy, which can be used as a template by other discovery efforts seeking to ensure their drug candidates can be developed for globally equitable and affordable access., Competing Interests: Competing interests: Edward J Griffen is a shareholder and Director of MedChemica Ltd and MedChemica Consultancy Ltd which are contractors of the ASAP AViDD U19 Center, in addition he is a shareholder in AstraZeneca plc and holds share options in Bugworks Inc. Pascale Boulet is an employee of the Drugs for Neglected Diseases initiative which is a contractor of the ASAP AViDD U19 Center. She has no further competing interests., (Copyright: © 2024 Griffen EJ et al.)

Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Abstract: Pulmonary hypertension (PH) is a haemodynamic disorder in which elevated blood pressure in the pulmonary circulation is caused by abnormal vascular tone. Despite advances in treatment, PH mortality remains high, and drug repurposing has been proposed as a mitigating approach. This article reviews the studies that have investigated drug repurposing as a viable option for PH. We provide an overview of PH and highlight pharmaceutical drugs with repurposing potential, based on limited evidence of their mechanisms of action. Moreover, studies have demonstrated the benefits of medicinal plants in PH, most of which are of Indian or Asian origin. Africa is a rich source of many medicinal plants that have been scientifically proven to counteract myriad pathologies. When perusing these studies, one will notice that some African medicinal plants can counteract the molecular pathways (e.g. proliferation, vasoconstriction, inflammation, oxidative stress and mitochondrial dysfunction) that are also involved in the pathogenesis of PH. We review the actions of these plants with actions applicable to PH and highlight that they could be repurposed as adjunct PH therapies. However, these plants have either never been tested in PH, or there is little evidence of their actions against PH. We therefore encourage caution, as more research is needed to study these plants further in experimental models of PH while acknowledging that the outcomes of such proof of-concept studies may not always yield promising findings. Regardless, this article aims to stimulate future research that could make timely contributions to the field., Study Synopsis: What the study adds. Pulmonary hypertension (PH) remains a fatal disease, and 80% of the patients live in developing countries where resources are scarce and specialised therapies are often unavailable. Drug repurposing is a viable option to try to improve treatment outcomes. Implications of the findings. We propose that another form of 'drug' repurposing is the use of medicinal plants, many of which have demonstrated benefits against pathological processes that are also key in PH, e.g. apoptosis, tumour-like growth of cells, proliferation, oxidative stress and mitochondrial dysfunction., (Copyright © 2024, Jacobs et al.)

The levels and activities of the DNA/RNA helicase schlafen11 (SLFN11) and the serine/threonine-protein kinase ataxia telangiectasia and Rad3-related protein (ATR) may determine cancer cell sensitivity to DNA damaging agents, including platinum drugs. Here, we studied the roles of SLFN11 and ATR in cisplatin resistance of ovarian cancer using cell lines displaying acquired or intrinsic cisplatin resistance. W1CR, the cisplatin-resistant subline of W1 ovarian cancer cells, displayed reduced SLFN11 levels. HDAC inhibition using entinostat returned an epigenetic downregulation of SLFN11 in W1CR cells, caused SLFN11 re-expression and re-sensitized these cells to cisplatin. Moreover, entinostat also sensitized intrinsically resistant EFO21 ovarian cancer cells to cisplatin by upregulating SLFN11. However, SLFN11 was not involved in cisplatin resistance in all other cell models. Thus, SLFN11 expression is not a general cisplatin resistance marker in ovarian cancer. In contrast, inhibition of the DNA damage repair master regulator ATR using sub-toxic concentrations of elimusertib sensitized parental cell lines as well as intrinsically resistant EFO21 cells to cisplatin, and fully reversed acquired cisplatin resistance in cisplatin-adapted sublines W1CR, A2780cis, and Kuramochi r CDDP 2000 . Mechanisms underlying ATR-mediated cisplatin resistance differed between the cell lines and included CHK1/WEE1 signaling and induction of homologous recombination. In conclusion, SLFN11 and ATR are involved in ovarian cancer cisplatin resistance. Although our data identify ATR as key target for tackling cisplatin resistance in ovarian cancer, future studies are needed to identify biomarkers that indicate, which individual ovarian cancers benefit from SLFN11 re-activation and/or ATR inhibition., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Mycetoma is a neglected invasive infection endemic in tropical and subtropical regions, presenting as a chronic subcutaneous inflammatory mass that can spread to deeper structures, leading to deformities, disabilities, and potentially mortality. The current treatment of eumycetoma, the fungal form of mycetoma, involves antifungal agents, such as itraconazole, combined with surgical intervention. However, this approach has limited success, with low cure rates and a high risk of recurrence. This study addresses to the urgent need for more effective therapeutics by designing and synthesising 47 diversely pharmacomodulated imidazo [1,2-b]pyridazine derivatives using a simple synthetic pathway with good yields and purity. Of these, 17 showed promising in vitro activity against Madurella mycetomatis, the prime causative agent of eumycetoma, with IC 50  ≤ 5 μM and demonstrated significantly lower cytotoxicity compared to standard treatments in NIH-3T3 fibroblasts. Notably, compound 14d exhibited an excellent activity with an IC 50 of 0.9 μM, in the same order then itraconazole (IC 50  = 1.1 μM), and achieved a favourable selectivity index of 16 compared to 0.8 for itraconazole. These promising results warrant further research to evaluate the clinical potential of these novel compounds as safer, more effective treatments for eumycetoma, thus addressing a profound gap in current therapeutic strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Small non-coding RNA or microRNA (miRNA) are critical regulators of eukaryotic cells. Dysregulation of miRNA expression and function has been linked to a variety of diseases including cancer. They play a complex role in cancers, having both tumour suppressor and promoter properties. In addition, a single miRNA can be involved in regulating several mRNAs or many miRNAs can regulate a single mRNA, therefore assessing these roles is essential to a better understanding in cancer initiation and development. Pancreatic cancer is a leading cause of cancer death worldwide, in part due to the lack of diagnostic tools and limited treatment options. The most common form of pancreatic cancer, pancreatic ductal adenocarcinoma (PDAC), is characterised by major genetic mutations that drive cancer initiation and progression. The regulation or interaction of miRNAs with these cancer driving mutations suggests a strong link between the two. Understanding this link between miRNA and PDAC progression may give rise to novel treatments or diagnostic tools. This review summarises the role of miRNAs in PDAC, the downstream signalling pathways that they play a role in, how these are being used and studied as therapeutic targets as well as prognostic/diagnostic tools to improve the clinical outcome of PDAC., (© 2024. The Author(s).)

In recent years, immunotherapy strategies based on immune checkpoint inhibitors have yielded good efficacy in colorectal cancer (CRC)especially in colorectal cancer with microsatellite instability-high. However, microsatellite-stable (MSS) CRCs account for about 85% of CRCs and are resistant to immunotherapy. Previous studies have shown that compared with MSS CRC, high microsatellite instability CRC possesses a higher frequency of mutations and can generate more neoantigens. Therefore, improving the sensitivity of immunotherapy to MSS CRC is a hot topic which is crucial for the treatment of MSS CRC. This review aims to discuss the factors contributing to MSS CRC insensitivity to immunotherapy and explored potential solutions to overcome immunotherapy resistance., (© The Author(s) 2024. Published by Oxford University Press on behalf of Fellowship of Postgraduate Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

PV-10 is a 10% formulation of rose bengal sodium that has potent immunotherapeutic and anti-cancer activity against various tumors, including metastatic melanoma and refractory neuroblastoma. Currently, PV-10 is undergoing clinical testing for refractory metastatic neuroendocrine cancer and melanomas. However, preclinical investigation of PV-10 activity and its mechanisms against phenotypically and molecularly diverse adult solid tumors had not been conducted. In a panel of human cell lines derived from breast, colorectal, head and neck, and testicular cancers, we demonstrated that PV-10 induces cytotoxicity by apoptotic and autophagic pathways involving caspase-mediated PARP cleavage, downregulation of SQSTM1/p62, and upregulation of beclin-1. Treatment with PV-10 also consistently reduced phosphorylation of WNK1, which has been implicated in cancer cell migration and autophagy inhibition. By wound healing assay, PV-10 treatment inhibited the migration of cancer cells. Finally, significant inhibition of tumor growth was also noted in tumor-bearing mice treated with PV-10 by intralesional or systemic administration. In addition to known PV-10-mediated tumor-specific cytotoxic effects, we identified the mechanisms of PV-10 and provide new insights into its effect on autophagy and metastasis. Our data provide essential mechanism-based evidence and biomarkers of activity to formulate clinical studies of PV-10 in the future.

Colorectal cancer (CRC) is a pervasive malignancy that stands as a prominent contributor to global cancer-related mortality. Among the numerous causative factors, the overexpression of human epidermal growth factor receptor 2 (HER2) is notably linked to CRC progression. Acronychia (A.) pedunculata has a longstanding history in folk medicine due to its multifaceted medicinal attributes. This study aimed to assess the potential of specific bioactive compounds derived from A. pedunculata for their inhibition of HER2 in CRC, utilizing in silico analysis. The compounds were systematically evaluated through a series of computational analyses. Drug-likeness assessment, pharmacokinetic evaluation, and toxicity analysis were conducted. Molecular docking studies were performed to investigate binding affinities with the HER2 target. Additionally, bioavailability radar analysis was employed to predict oral bioavailability, while molecular target prediction provided insights into potential protein interactions. All 12 compounds demonstrated favorable drug-likeness properties and adherence to Lipinski's rule of five, indicative of the potential for good oral bioavailability. Four compounds were found to have no toxicological endpoints. Molecular docking revealed two compounds, namely caryophylla-4 (14), 8 (15)-dien-5alpha-ol and (-)-globulol, which showed promising binding affinities between several compounds and HER2. From this study, two leads were identified from A. pedunculata. Further experimental studies are required to validate the action of leads., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Pharmacy and Bioallied Sciences.)

Introduction: Chronic pancreatitis (CP) is a persistent, recurrent, and progressive disorder that is characterized by chronic inflammation and irreversible fibrosis of the pancreas. It is associated with severe morbidity, resulting in intense abdominal pain, diabetes, exocrine and endocrine dysfunction, and an increased risk of pancreatic cancer. The etiological factors are diverse and the major risk factors include smoking, chronic alcoholism, as well as other environmental and genetic factors. The treatment and management of CP is challenging, and no definitive curative therapy is currently available., Areas Covered: This review paper aims to provide an overview of the different cell types in the pancreas that is known to mediate disease progression and outline potential novel therapeutic approaches and drug targets that may be effective in treating and managing CP. The information presented in this review was obtained by conducting a NCBI PubMed database search, using relevant keywords., Expert Opinion: In recent years, there has been an increased interest in the development of novel therapeutics for CP. A collaborative multi-disciplinary approach coupled with a consistent funding for research can expedite progress of translating the findings from bench to bedside.

Purpose of Review: This review seeks to identify and describe novel genetic and protein targets and their associated therapeutics currently being used or studied in the treatment of acute myeloid leukemia (AML)., Recent Findings: Over the course of the last 5-6 years, several targeted therapies have been approved by the FDA, for the treatment of both newly diagnosed as well as relapsed/refractory AML. These novel therapeutics, as well as several others currently under investigation, have demonstrated activity in AML and have improved outcomes for many patients. Patient outcomes in AML have slowly improved over time, though for many patients, particularly elderly patients or those with relapsed/refractory disease, mortality remains very high. With the identification of several molecular/genetic drivers and protein targets and development of therapeutics which leverage those mechanisms to target leukemic cells, outcomes for patients with AML have improved and continue to improve significantly., (© 2024. The Author(s).)

The link between elevated LDL-C, low HDL-C, elevated triglycerides, and an increased risk for cardiovascular disease has solidified over the past decades. Concomitantly, the number of agents to treat dyslipidemia proliferated in clinical trials, proving or refuting their clinical efficacy. Many of these agents' role in reducing cardiovascular disease morbidity and mortality is now clear. Recently, there has been an explosion in emerging therapeutics for the primary and secondary prevention of cardiovascular disease through the control of dyslipidemia. This article reviews standard, new, and emerging treatments for hyperlipidemia., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The survival rate of pediatric acute myeloid leukemia (pAML) is currently around 60%. While survival has slowly increased over the past few decades, the development of novel agents likely to further improve survival for this heterogeneous patient population has been limited by gaps in the pAML pre-clinical pipeline. One of the major hurdles in evaluating new agents for pAML is the lack of pAML patient-derived xenograft (PDX) models. Unlike solid tumors and other types of leukemias, AML is notoriously hard to establish in mouse models, likely due in part to the need for specific human microenvironment elements. Our laboratory at TCH/BCM addressed this gap by establishing a systematic PDX workflow, leveraging advanced immunodeficient hosts and capitalizing on our high volume of pAML patients and close coordination between labs and clinical sections. Patients treated at TCH are offered the chance to participate in specimen banking protocols that allow blood and bone marrow collection as well as the collection of relevant clinical data. All patients who consent and have samples available are trialed for PDX development. In addition, samples from the Children's Oncology Group (COG) are also trialed for PDX generation. Serially transplanting PDX models are validated using short tandem repeat (STR) and characterized using both targeted DNA/RNA next generation sequencing and RNAseq. As of March 2023, this systematic approach has resulted in 26 serially transplanting models. Models have been shared with requesting labs to facilitate external pAML pre-clinical studies. Available PDX models can be located through the BCM PDX Portal. We expect our growing PDX resource to make a significant contribution to expediting the testing of promising novel therapeutics for pAML.

Background: Arginase 1 Deficiency (ARG1-D) is a rare debilitating, progressive, inherited, metabolic disease characterized by marked increases in plasma arginine (pArg) and its metabolites, with increased morbidity, substantial reductions in quality of life, and premature mortality. Effective treatments that can lower arginine and improve clinical outcomes is currently lacking. Pegzilarginase is a novel human arginase 1 enzyme therapy. The present trial aimed to demonstrate efficacy of pegzilarginase on pArg and key mobility outcomes., Methods: This Phase 3 randomized, double-blind, placebo-controlled, parallel-group clinical trial (clinicaltrials.govNCT03921541, EudraCT 2018-004837-34), randomized patients with ARG1-D 2:1 to intravenously/subcutaneously once-weekly pegzilarginase or placebo in conjunction with their individualized disease management. It was conducted in 7 countries; United States, United Kingdom, Canada, Austria, France, Germany, Italy. Primary endpoint was change from baseline in pArg after 24 weeks; key secondary endpoints were change from baseline at Week 24 in Gross Motor Function Measure part E (GMFM-E) and 2-min walk test (2MWT). Full Analysis Set was used for the analyses., Findings: From 01 May 2019 to 29 March 2021, 32 patients were enrolled and randomized (pegzilarginase, n = 21; placebo, n = 11). Pegzilarginase lowered geometric mean pArg from 354.0 μmol/L to 86.4 μmol/L at Week 24 vs 464.7 to 426.6 μmol/L for placebo (95% CI: -67.1%, -83.5%; p  < 0.0001) and normalized levels in 90.5% of patients (vs 0% with placebo). In addition, clinically relevant functional mobility improvements were demonstrated with pegzilarginase treatment. These effects were sustained long-term through additional 24 weeks of subsequent exposure. Pegzilarginase was well-tolerated, with adverse events being mostly transient and mild/moderate in severity., Interpretation: These results support pegzilarginase as the first potential treatment to normalize pArg in ARG1-D and achieve clinically meaningful improvements in functional mobility., Funding: Aeglea BioTherapeutics., Competing Interests: Dr Sanchez Russo has received travel support from Aeglea BioTherapeutics. Dr Gasperini has served on advisory boards for Aeglea BioTherapeutics and Immedica Pharma AB. Dr Neuman and Dr Bubb are former employees of Aeglea BioTherapeutics and owns stocks or equity in the company. Dr Sloan is former employee of Aeglea BioTherapeutics. Dr Diaz has received travel support from and served on advisory boards and speakers bureaus for Aeglea BioTherapeutics. Dr Enns has served on advisory boards for Aeglea BioTherapeutics, and performed consulting services for Horizon Therapeutics. Aeglea BioTherapeutics funded the trial and provided medical writing support. Immedica Pharma provided scientific editing and medical writing support., (© 2023 Immedica Pharma AB.)

Chemical probes are essential for academic research and target validation for disease identification. They facilitate drug discovery, target function investigation, and translation studies. A chemical probe provides starting material that can accelerate therapeutic values and safety measures for identifying any biological target in drug discovery. Essential read outs depend on their versatility in biochemical testing, proving the hypothesis, selectivity, specificity, affinity towards the target site, and valuable in new therapeutic approaches. Disease management will depend upon chemical probes as a primitive tool to ascertain the physicochemical stability for in vivo and in vitro studies useful for clinical trials and industrial application in the future. For cancer research, bacterial infection, and neurodegenerative disorders, chemical probes are integrated circuits which are on pipeline for the drug discovery process Furthermore, pharmacological modulators incorporate activators, crosslinkers, degraders, and inhibitors. Reports accessed depend on their structural, mechanical, biochemical, and pharmacological characterization in drug discovery research. The perspective for designing any chemical probes concludes with the utilization of drug discovery and identification of the potential target. It focuses mainly on evidence-based studies and produces promising results in successfully delivering novel therapeutics to treat cancers and other disorders at the target site. Moreover, natural product pharmacophores like rapamycin, cephalosporin, and α-lactamase are utilized for drug discovery. Chemical probes revolutionize computational-based study design depending on identifying novel targets within the database framework. Chemical probes are the clinical answers for drug development and goforward tools in solving other riddles for scientists and researchers working in this industries., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Cervical cancer is the fourth most common cause of cancer-related death worldwide. High-risk locally advanced or recurrent/metastatic cervical cancers have a poor prognosis with routine treatments. The objective of this study is to analyze the data available in the literature on therapies and molecules currently in use to improve the prognosis of recurrent cervical cancer., Areas Covered: An extensive literature search was conducted by authors to identify relevant trials on various databases. Articles in English published until September 2023 that investigate different pharmacotherapy strategies for the treatment of recurrent cervical cancer, were included. Results of various pharmacological regimens including different combinations of chemotherapy, immune checkpoint inhibitors, DNA damage repair inhibitors and antibody-drug conjugates were analyzed., Expert Opinion: In recent years, there have been significant improvements in the outcomes of recurrent/metastatic cervical cancer. However, these improvements do not address the unmet need in terms of oncological outcomes. The introduction of immunotherapy and targeted therapies showed advantages in cervical cancer patients. New therapies and combination strategies must be implemented. Centralization of care and enrollment in clinical trials are of paramount importance. Primary and secondary prevention remains the fundamental goal to reduce the burden of cervical cancer.

Ninety-five years after Fleming's discovery of penicillin, a bounty of antibiotic compounds have been discovered, modified, or synthesised. Diversification of target sites, improved stability and altered activity spectra have enabled continued antibiotic efficacy, but overwhelming reliance and misuse has fuelled the global spread of antimicrobial resistance (AMR). An estimated 1.27 million deaths were attributable to antibiotic resistant bacteria in 2019, representing a major threat to modern medicine. Although antibiotics remain at the heart of strategies for treatment and control of bacterial diseases, the threat of AMR has reached catastrophic proportions urgently calling for fresh innovation. The last decade has been peppered with ground-breaking developments in genome sequencing, high throughput screening technologies and machine learning. These advances have opened new doors for bioprospecting for novel antimicrobials. They have also enabled more thorough exploration of complex and polymicrobial infections and interactions with the healthy microbiome. Using models of infection that more closely resemble the infection state in vivo, we are now beginning to measure the impacts of antimicrobial therapy on host/microbiota/pathogen interactions. However new approaches are needed for developing and standardising appropriate methods to measure efficacy of novel antimicrobial combinations in these contexts. A battery of promising new antimicrobials is now in various stages of development including co-administered inhibitors, phages, nanoparticles, immunotherapy, anti-biofilm and anti-virulence agents. These novel therapeutics need multidisciplinary collaboration and new ways of thinking to bring them into large scale clinical use., (Copyright © 2024. Published by Elsevier Inc.)

Liquid-liquid phase separation (LLPS) is a novel principle for interpreting precise spatiotemporal coordination in living cells through biomolecular condensate (BMC) formation via dynamic aggregation. LLPS changes individual molecules into membrane-free, droplet-like BMCs with specific functions, which coordinate various cellular activities. The formation and regulation of LLPS are closely associated with oncogenesis, tumor progressions and metastasis, the specific roles and mechanisms of LLPS in tumors still need to be further investigated at present. In this review, we comprehensively summarize the conditions of LLPS and identify mechanisms involved in abnormal LLPS in cancer processes, including tumor growth, metastasis, and angiogenesis from the perspective of cancer hallmarks. We have also reviewed the clinical applications of LLPS in oncologic areas. This systematic summary of dysregulated LLPS from the different dimensions of cancer hallmarks will build a bridge for determining its specific functions to further guide basic research, finding strategies to intervene in LLPS, and developing relevant therapeutic approaches., (© 2023. The Author(s).)

Introduction: Bile duct cancer (cholangiocarcinoma, CCA) has a poor prognosis for patients, and despite recent advances in targeted therapies for other cancer types, it is still treated with standard chemotherapy. Anaplastic lymphoma kinase (ALK) has been shown to be a primary driver of disease progression in lung cancer, and ALK inhibitors are effective therapeutics in aberrant ALK-expressing tumors. Aberrant ALK expression has been documented in CCA, but the use of ALK inhibitors has not been investigated. Using CCA cell lines and close-to-patient primary cholangiocarcinoma cells, we investigated the potential for ALK inhibitors in CCA., Methods: ALK, cMET, and ROS1 expression was determined in CCA patient tissue by immunohistochemistry and digital droplet polymerase chain reaction, and that in cell lines was determined by immunoblot and immunofluorescence. The effect on cell viability and mechanism of action of ALK, cMet, and ROS1 inhibitors was determined in CCA cell lines. To determine whether ceritinib could affect primary CCA cells, tissue was taken from four patients with biliary tract cancer, without ALK rearrangement, mutation, or overexpression, and grown in three-dimensional tumor growth assays in the presence or absence of humanized mesenchymal cells., Results: ALK and cMet but not ROS were both upregulated in CCA tissues and cell lines. Cell survival was inhibited by crizotinib, a c-met/ALK/ROS inhibitor. To determine the mechanism of this effect, we tested c-Met-specific and ALK/ROS-specific inhibitors, capmatinib and ceritinib, respectively. Whereas capmatinib did not affect cell survival, ceritinib dose-dependently inhibited survival in all cell lines, with IC 50 ranging from 1 to 9 µM and co-treatments with gemcitabine and cisplatin further sensitized cells, with IC 50 ranging from IC 50 0.60 to 2.32 µM. Ceritinib did not inhibit cMet phosphorylation but did inhibit ALK phosphorylation. ALK was not mutated in any of these cell lines. Only ceritinib inhibited 3D growth of all four patient samples below mean peak serum concentration, in the presence and absence of mesenchymal cells, whereas crizotinib and capmatinib failed to do this. Ceritinib appeared to exert its effect more through autophagy than apoptosis., Discussion: These results indicate that ceritinib or other ALK/ROS inhibitors could be therapeutically useful in cholangiocarcinoma even in the absence of aberrant ALK/ROS1 expression., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Myint, Sueca-Comes, Collier, Balasubramanian, Venkatraman, Gordan, Zaitoun, Mukherjee, Arora, Larbcharoensub, Suriyonplengsaeng, Wongprasert, Janvilisri, Gomez, Grabowska, Tohtong, Bates and Yacqub-Usman.)

Familial hypercholesterolemia (FH) is a genetically transmitted disorder. It shows an autosomal dominant mode of inheritance. It is a metabolic disorder. Mutation in chromosome 19 leads to this disorder. Chromosome 19 codes data for low-density lipoprotein (LDL) receptor (LDLR). LDLR either reduces increased LDL levels from the circulation or maintains a normal level of LDL. It precipitates the risk of cardiovascular disease at an early age. Characteristic features of FH are elevated levels of LDL in the blood because of sudden changes in LDLR, which causes a decrease in the clearance of LDL from the blood. Plaque gets deposited in the lumen of the arteries, called atherosclerosis, which occurs at an early young age. If both genes are affected then it is homozygous FH (HoFH); such a case is very rare. When a single gene is affected then that condition is known as heterozygous FH (HeFH). HoFH comes up with more severe cardiac disease than HeFH at an early age. The major cause of FH is a mutation in the LDLR gene while other causes include mutation in various genes like apolipoprotein B (apo B), proprotein convertase subtilisin/kexin type 9 (PCSK9), LDLR adaptor protein 1 (LDLRAP 1). In order to prevent cardiovascular crises due to FH, it must be diagnosed early and treated effectively. With increasing research and advances in medical sciences, many kinds of current and novel therapies are emerging that aim to reduce the level of LDL in blood., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Suryawanshi et al.)

Antibiotics are the most efficient type of therapy developed in the twentieth century. From the early 1960s to the present, the rate of discovery of new and therapeutically useful classes of antibiotics has significantly decreased. As a result of antibiotic use, novel strains emerge that limit the efficiency of therapies in patients, resulting in serious consequences such as morbidity or mortality, as well as clinical difficulties. Antibiotic resistance has created major concern and has a greater impact on global health. Horizontal and vertical gene transfers are two mechanisms involved in the spread of antibiotic resistance genes (ARGs) through environmental sources such as wastewater treatment plants, agriculture, soil, manure, and hospital-associated area discharges. Mobile genetic elements have an important part in microbe selection pressure and in spreading their genes into new microbial communities; additionally, it establishes a loop between the environment, animals, and humans. This review contains antibiotics and their resistance mechanisms, diffusion of ARGs, prevention of ARG transmission, tactics involved in microbiome identification, and therapies that aid to minimize infection, which are explored further below. The emergence of ARGs and antibiotic-resistant bacteria (ARB) is an unavoidable threat to global health. The discovery of novel antimicrobial agents derived from natural products shifts the focus from chemical modification of existing antibiotic chemical composition. In the future, metagenomic research could aid in the identification of antimicrobial resistance genes in the environment. Novel therapeutics may reduce infection and the transmission of ARGs., (© 2023. Institute of Microbiology, Academy of Sciences of the Czech Republic, v.v.i.)

Background and Objectives: Immune thrombotic thrombocytopenic purpura (iTTP) is a rare, but potentially fatal blood disease, resulting from autoantibodies against A Disintegrin and Metalloprotease with ThromboSpondin Type 1 Repeats, 13 (ADAMTS13). While major progress has been made in past decades concerning early diagnosis and management of iTTP, the mechanisms underlying the formation and the mechanism of action of these autoantibodies against ADMATS13 are still unknown. This review will provide a narrative review of pathogenesis and novel therapeutics of iTTP., Methods: We did PubMed literature search using a combination of thrombotic thrombocytopenic purpura and treatment or pathogenesis from 1955 to November 2022. A total of 4,767 articles with full text were found and only relevant articles in English were further reviewed and summarized., Key Content and Findings: We found that the primary mechanism underlying severe ADAMTS13 deficiency in patients with iTTP is autoantibody-mediated inhibition and/or accelerated clearance of ADAMTS13 metalloprotease. Other factors including allosteric regulation and post-translational modifications (i.e., glycosylation and citrullination, and arginine methylation, etc.) may affect ADAMTS13 secretion and function and also contribute to the pathogenesis of iTTP. The standard of care for iTTP today consists of therapeutic plasma exchange, anti-von Willebrand factor (vWF) caplacizumab, and immunosuppressives (e.g., corticosteroids and rituximab), known as the triple therapy, which has significantly reduced exacerbation and mortality rates., Conclusions: We hope that the information provided in the review article helps better understand the pathogenesis of iTTP, which may guide design novel and more effective therapeutics for this potentially fatal disorder., Competing Interests: Both authors have completed the ICMJE uniform disclosure form (available at https://aob.amegroups.com/article/view/10.21037/aob-22-29/coif). The series “Thrombotic Thrombocytopenic Purpura” was commissioned by the editorial office without any funding or sponsorship. XLZ served as the unpaid Guest Editor of the series and serves as an unpaid Editorial Board member of Annals of Blood from March 2022 to February 2024. XLZ receives consulting fees from Alexion, Sanofi and Takeda, and receives grants from National Institutes of Health (Nos. HL126724, HL144552, and HL157975-01A1) and Answering TTP Foundation. XLZ is a consultant or a member of advisory boards for Alexion, Sanofi, and Takeda, as well as a co-founder of Clotsolution. XLZ also serves in several journal editorial boards (CJTH, JCTP, Arch Path Lab Med, Genomics, JCM, Diagnostics, Genomics and World Federation of Chinese Med). The authors have no other conflicts of interest to declare.

Oxidative stress is a common characteristic of psychiatric, neurological, and neurodegenerative disorders. Therefore, compounds that are neuroprotective and reduce oxidative stress may be of interest as novel therapeutics. Phenolic, flavonoid and anthocyanin content, ORAC and DPPH free radical scavenging, and Cu 2+ and Fe 2+ chelating capacities were examined in variations (fresh/capsule) of Queen Garnet plum (QGP, Prunus salicina ), black pepper ( Piper nigrum ) clove ( Syzygium aromaticum ), elderberry ( Sambucus nigra ), lemon balm ( Melissa officinalis ) and sage ( Salvia officinalis ), plus two blends ( Astralagus membranaceus -lemon balm-rich, WC and R8). The ability of samples to prevent and treat H 2 O 2 -induced oxidative stress in SH-SY5Y cells was investigated. Pre-treatment with WC, elderberry, QGP, and clove prevented the oxidative stress-induced reduction in cell viability, demonstrating a neuroprotective effect. Elderberry increased cell viability following oxidative stress induction, demonstrating treatment effects. Clove had the highest phenolic and flavonoid content, DPPH, and Cu 2+ chelating capacities, whereas QGP and elderberry were highest in anthocyanins. Black pepper had the highest ORAC and Fe 2+ chelating capacity. These findings demonstrate that plant extracts can prevent and treat oxidative stress-induced apoptosis of neuron-like cells in vitro. Further research into phytochemicals as novel therapeutics for oxidative stress in the brain is needed.

Lennox-Gastaut syndrome is a severe drug-resistant developmental and epileptic encephalopathy with slow spike and wave on EEG (DEE-SSW) composing about 1-2% of epilepsy patients. Seizures in DEE-SSW are caused by a variety of etiologies, and there is a large unmet treatment need as seizures are usually treatment-resistant and individuals are often unable to function independently. The updated definition by the International League Against Epilepsy has established formal diagnostic criteria allowing for more uniform diagnosis. This article provides a review of typical medication management and treatment strategies, including new and developing surgical approaches. Future directions in treatment include expanding genetic testing with the potential for gene therapy and continuously improving surgical options with the goal to prevent progression to DEE-SSW., (© 2023. The American Society for Experimental Neurotherapeutics, Inc.)

Antibody-drug conjugates (ADCs) are at the forefront of the drug development revolution occurring in oncology. Formed from three main components-an antibody, a linker molecule, and a cytotoxic agent ("payload"), ADCs have the unique ability to deliver cytotoxic agents to cells expressing a specific antigen, a great leap forward from traditional chemotherapeutic approaches that cause widespread effects without specificity. A variety of payloads can be used, including most frequently microtubular inhibitors (auristatins and maytansinoids), as well as topoisomerase inhibitors and alkylating agents. Finally, linkers play a critical role in the ADCs' effect, as cleavable moieties that serve as linkers impact site-specific activation as well as bystander killing effects, an upshot that is especially important in solid tumors that often express a variety of antigens. While ADCs were initially used in hematologic malignancies, their utility has been demonstrated in multiple solid tumor malignancies, including breast, gastrointestinal, lung, cervical, ovarian, and urothelial cancers. Currently, six ADCs are FDA-approved for the treatment of solid tumors: ado-trastuzumab emtansine and trastuzumab deruxtecan, both anti-HER2; enfortumab-vedotin, targeting nectin-4; sacituzuzmab govitecan, targeting Trop2; tisotumab vedotin, targeting tissue factor; and mirvetuximab soravtansine, targeting folate receptor-alpha. Although they demonstrate utility and tolerable safety profiles, ADCs may become ineffective as tumor cells undergo evolution to avoid expressing the specific antigen being targeted. Furthermore, the current cost of ADCs can be limiting their reach. Here, we review the structure and functions of ADCs, as well as ongoing clinical investigations into novel ADCs and their potential as treatments of solid malignancies.

Autotaxin (ATX) is a secreted enzyme that produces extracellular lysophosphatidate in physiological wound healing. ATX is overexpressed in many cancers to promote growth, metastasis, and treatment resistance. However, ATX expression is very low in breast cancer cells, and is instead secreted by the tumor microenvironment (TME). Paracrine ATX expression, and its effects on tumor progression, has not been robustly studied in human breast tumors. In this study, ATX expression was analyzed in over 5000 non-metastatic breast cancers from databases TCGA, METABRIC and GSE96058, dichotomized by the median. Gene set enrichment analysis (GSEA) and the xCell algorithm investigated biological functions of ATX and correlation to TME cell populations. TME ATX production was verified by single cell RNA sequencing. The highest ATX expression occurred in endothelial cells and cancer-associated fibroblasts ( P <0.0001). High tumor ATX expression correlated to increased adipocyte, fibroblast, and endothelial cell fractions ( P <0.01), and GSEA demonstrated enriched immune system, tumor suppressor, pro-survival, stemness, and pro-inflammatory signaling in multiple gene sets. Tumor mutational burden was decreased, Ki67 scores were decreased, tumor infiltrating immune cell populations increased, and immune cytolytic activity scores increased (all P <0.01) for ATX-high tumors. Overall survival trends favored ATX-high tumors (hazard ratios 0.75-0.80). In summary, in human breast cancers, ATX is produced by the TME, and in non-metastatic tumors, high levels correlate with an anti-tumor phenotype. Because pre-clinical models use aggressive pro-metastatic cell lines where ATX-mediated signaling promotes tumorigenesis, further research is required to verify an anti-to-pro-tumor phenotype switch with breast cancer progression and/or treatment resistance., Competing Interests: None., (AJCR Copyright © 2023.)

With the increasing incidence of diabetes, diabetic kidney disease has become a major cause of chronic kidney disease. The role of the gut microbiota in diabetes and its related complications have been extensively investigated; the modulatory effect of the gut microbiota on the host depends on several gut microbial metabolites, particularly short-chain fatty acids, secondary bile acids, and trimethylamine N-oxide. In this review, we focused on the evidence related to the pathogenic role of each of the gut microbial metabolites in diabetic nephropathy. The main novel therapies targeting the gut microbiota include probiotics, dietary prebiotics, synbiotic supplements, and faecal microbiota transplants, although there is no standard treatment principle. Further research is therefore needed to elucidate the link between gut microbes and diabetic nephropathy, and more therapeutic targets should be explored to treat diabetic nephropathy with dysbiosis of the gut microbes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Tian, Wang, Zhao, Sun and Yang.)

Introduction: Pulmonary arterial hypertension (PAH) is a progressive and life-threatening disease. Approved treatment options currently primarily target abnormal cell signaling pathways involved in vasoconstriction and proliferation, such as those mediated by prostacyclin, cyclic guanosine monophosphate, and endothelin., Areas Covered: Recent advancements have led to new applications and modes of delivery of currently approved PAH medications. At the same time, novel drugs targeting specific molecular pathways involved in PAH pathogenesis have been developed and are being investigated in clinical trials. This review summarizes investigational drug trials for PAH gathered from a comprehensive search using PubMed and ClinicalTrials.gov between 2003 and 2023. It includes both currently approved medications studied at different doses or new administration forms and experimental drugs that have not yet been approved., Expert Opinion: Approved treatments for PAH target imbalances in pulmonary vasoactive pathways that work primarily on enhancing pulmonary vasodilation with less salient effects on pulmonary vascular remodeling. The advent of more locally acting inhaled medications offers additional therapeutic options that may improve the ease of drug delivery and reduce adverse systemic effects. The more recent emphasis on developing and applying therapeutics that directly impact the aberrant signaling pathways implicated in PAH appears more likely to advance the treatment of this devastating disease.

Myeloproliferative neoplasms (MPNs) are a group of clonal hematologic malignancies that include polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). MPNs are characterized by activating mutations in the JAK/STAT pathway and an increased risk of transformation to an aggressive form of acute leukemia, termed MPN-blast phase (MPN-BP). MPN-BP is characterized by the presence of ⩾20% blasts in the blood or bone marrow and is almost always preceded by an accelerated phase (MPN-AP) defined as ⩾10-19% blasts in the blood or bone marrow. These advanced forms of disease are associated with poor prognosis with a median overall survival (mOS) of 3-5 months in MPN-BP and 13 months in MPN-AP. MPN-AP/BP has a unique molecular landscape characterized by increased intratumoral complexity. Standard therapies used in de novo acute myeloid leukemia (AML) have not demonstrated improvement in OS. Allogeneic hematopoietic stem cell transplant (HSCT) remains the only curative therapy but is associated with significant morbidity and mortality and infrequently utilized in clinical practice. Therefore, an urgent unmet need persists for effective therapies in this advanced phase patient population. Here, we review the current management and future directions of therapy in MPN-AP/BP., (© The Author(s), 2023.)

Lysophosphatidic acid receptors (LPARs) are six G-protein-coupled receptors that mediate LPA signaling to promote tumorigenesis and therapy resistance in many cancer subtypes, including breast cancer. Individual-receptor-targeted monotherapies are under investigation, but receptor agonism or antagonism effects within the tumor microenvironment following treatment are minimally understood. In this study, we used three large, independent breast cancer patient cohorts (TCGA, METABRIC, and GSE96058) and single-cell RNA-sequencing data to show that increased tumor LPAR1 , LPAR4 , and LPAR6 expression correlated with a less aggressive phenotype, while high LPAR2 expression was particularly associated with increased tumor grade and mutational burden and decreased survival. Through gene set enrichment analysis, it was determined that cell cycling pathways were enriched in tumors with low LPAR1 , LPAR4 , and LPAR6 expression and high LPAR2 expression. LPAR levels were lower in tumors over normal breast tissue for LPAR1 , LPAR3 , LPAR4 , and LPAR6 , while the opposite was observed for LPAR2 and LPAR5 . LPAR1 and LPAR4 were highest in cancer-associated fibroblasts, while LPAR6 was highest in endothelial cells, and LPAR2 was highest in cancer epithelial cells. Tumors high in LPAR5 and LPAR6 had the highest cytolytic activity scores, indicating decreased immune system evasion. Overall, our findings suggest that potential compensatory signaling via competing receptors must be considered in LPAR inhibitor therapy.

The stellate ganglion block (SGB) procedure has been used successfully for over twelve years to treat thousands of patients suffering from posttraumatic stress disorder (PTSD). Level 1b evidence supports this use of SGB, but no studies to date have reported specifically on anxiety symptom improvements following SGB. We collected Generalized Anxiety Disorder questionnaire (GAD-7) scores pre-procedure and at 1-week and 1-month post-procedure from 285 patients. The mean baseline GAD-7 score of 15.9 (indicating severe anxiety) declined significantly following SGB treatment. Changes in GAD-7 scores ≥ 4 were considered clinically meaningful. From baseline to 1 week, the GAD-7 scores dropped by 9.0 points (95% CI = 8.3-9.7, p < 0.001, d = 1.8), with 211 (79.6%) patients demonstrating clinically meaningful improvement. Furthermore, from baseline to 1 month, the GAD-7 scores dropped by 8.3 points (95% CI = 7.6-9.0, p < 0.001, d = 1.7), with 200 (75.5%) patients demonstrating clinically meaningful improvement. The stellate ganglion block treatment resulted in a decrease of GAD-7 scores of over twice the minimal clinically important difference in treating anxiety for at least 1 month following SGB. Given the results from this retrospective observational study, larger prospective studies should be conducted to determine the effects of SGB treatment as a novel therapeutic treatment for generalized anxiety disorder and other anxiety disorders.

Opinion Statement: In 2023, breast cancer brain metastases (BCBrM) remain a major clinical challenge gaining well-deserved attention. Historically managed with local therapies alone, systemic therapies including small molecule inhibitors and antibody-drug conjugates (ADCs) have shown unprecedented activity in recent trials including patients with brain metastases. These advancements stem from efforts to include patients with stable and active BCBrM in early- and late-phase trial design. Tucatinib added to trastuzumab and capecitabine improves intracranial and extracranial progression-free survival and overall survival in stable and active human epidermal growth factor receptor 2 (HER2+)-positive brain metastases. Trastuzumab deruxtecan (T-DXd) has both shown impressive intracranial activity in stable and active HER2+ BCBrMs challenging historical thinking of ADCs' inability to penetrate the central nervous system (CNS). T-DXd has shown potent activity in HER2-low (immunohistochemistry scores of 1+ or 2+, non-amplified by fluorescence in situ hybridization) metastatic breast cancer and will be studied in HER2-low BCBrM as well. Novel endocrine therapies including oral selective estrogen downregulators (SERDs) and complete estrogen receptor antagonists (CERANs) are being studied in hormone receptor-positive BCBrM clinical trials due to robust intracranial activity in preclinical models. Triple-negative breast cancer (TNBC) brain metastases continue to portend the worst prognosis of all subtypes. Clinical trials leading to the approval of immune checkpoint inhibitors have enrolled few BCBrM patients leading to a lack of understanding of immunotherapies contribution in this subgroup. Data surrounding the use of poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors in patients with germline BRCA mutation carriers with CNS disease is hopeful. ADCs including those targeting low-level HER2 expression and TROP2 are under active investigation in triple-negative BCBrMs., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

We have used an integrated computational approach to explore the role of vitamin C and vitamin D in preventing aggregation of Fibrinogen A alpha-chain (FGA cter ) protein responsible for renal amyloidosis. We modelled structures of E524K / E526K mutants of FGA cter protein and examined the potential interactions of these mutants with vitamin C and vitamin D3. Interaction of these vitamins at the amyloidogenic site may prevent the intermolecular interaction required for amyloid formation. The binding free energy values of vitamin C and vitamin D3 for E524K FGA cter and E526K FGA cter are - 67.12 ± 30.46 kJ/mole and - 79.45 ± 26.12 kJ/mol, respectively. Experimental studies using Congo red absorption, aggregation index studies and AFM imaging show encouraging results. The AFM images of E526K FGA cter contained more extensive and higher protofibril aggregates, whereas, in the presence of vitamin D3, small monomeric and oligomeric aggregates were observed. Overall, the works provide interesting results about vitamin C and D role in preventing renal amyloidosis., Competing Interests: Declaration of Interest Statement The authors declared no conflict of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Antimicrobial resistance is a phenomenon that the present-day world is witnessing that poses a serious threat to global health. The decline in the development of novel therapeutics over the last couple of decades has exacerbated the situation further. In this scenario, the pursuit of new alternative therapeutics to commonly used antibiotics has gained predominance amongst researchers across the world. Antimicrobial peptides (AMPs) from natural sources have drawn significant interest in the recent years as promising pharmacological substitutes over the conventional antibiotics. The most notable advantage of AMPs is that microorganisms cannot develop resistance to them. Insects represent one of the potential sources of AMPs, which are synthesized as part of an innate immune defence against invading pathogens. AMPs from different insects have been extensively studied, and silkworm is one of them. Diverse classes of AMPs (including attacins, cecropins, defensins, enbocins, gloverins, lebocins and moricins) were identified from silkworm that exhibit antimicrobial property against bacteria, fungi and viruses, indicating their potential therapeutic benefits. This review briefs about the immune responses of silkworm to invading pathogens, the isolation of AMPs from silkworms, AMPs reported in silkworms and their activity against various microorganisms.

Purpose of Review: The AXL signaling pathway is associated with tumor growth as well as poor prognosis in cancer. Here, we highlight recent strategies for targeting AXL in the treatment of solid and hematological malignancies., Recent Findings: AXL is a key player in survival, metastasis, and therapeutic resistance in many cancers. A range of AXL-targeted therapies, including tyrosine kinase inhibitors, monoclonal antibodies, antibody-drug conjugates, and soluble receptors, have entered clinical development. Notably, AXL inhibitors in combination with immune checkpoint inhibitors demonstrate early promise; however, further understanding of predictive biomarkers and treatment sequencing is necessary. Based on its role in tumor growth and drug resistance, AXL represents a promising therapeutic target in oncology. Results from ongoing clinical trials will provide valuable insights into the role of AXL inhibitors, both as single agents and in combination with other therapies., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Myeloproliferative neoplasms (MPNs) are clonal disorders of hematopoietic stem cells; these include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). MPNs are inflammatory cancers, wherein the malignant clone generates cytokines that sustain the inflammatory drive in a self-perpetuating vicious cycle. The course of MPNs follows a biological continuum, that is, from early cancer stages (ET/PV) to advanced myelofibrosis as well as impending leukemic transformation. MPN-related symptoms, e.g., fatigue, general weakness, and itching, are caused by inflammatory cytokines. Thrombosis and bleeding are also exacerbated by inflammatory cytokines in patients with MPN. Until recently, the primary objective of ET and PV therapy was to increase survival rates by preventing thrombosis. However, several medications have recently demonstrated the ability to modify the course of the disease; symptom relief is expected for most patients. In addition, there is increasing interest in the active treatment of patients at low risk with PV and ET. This review focuses on the ET/PV treatment strategies as well as novel treatment options for clinical development.

Current treatment of Chlamydia trachomatis using doxycycline and azithromycin introduces detrimental side effects on the host's microbiota. As a potential alternative treatment, the myxobacterial natural product sorangicin A (SorA) blocks the bacterial RNA polymerase. In this study we analyzed the effectiveness of SorA against C. trachomatis in cell culture, and explanted fallopian tubes and systemic and local treatment in mice, providing also pharmacokinetic data on SorA. Potential side effects of SorA on the vaginal and gut microbiome were assessed in mice and against human-derived Lactobacillus species. SorA showed minimal inhibitory concentrations of 80 ng/mL (normoxia) to 120 ng/mL (hypoxia) against C. trachomatis in vitro and was eradicating C. trachomatis at a concentration of 1 µg/mL from fallopian tubes. In vivo, SorA reduced chlamydial shedding by more than 100-fold within the first days of infection by topical application corresponding with vaginal detection of SorA only upon topical treatment, but not after systemic application. SorA changed gut microbial composition during intraperitoneal application only and did neither alter the vaginal microbiota in mice nor affect growth of human-derived lactobacilli. Additional dose escalations and/or pharmaceutical modifications will be needed to optimize application of SorA and to reach sufficient anti-chlamydial activity in vivo.

As an essential micronutrient, manganese plays an important role in the physiological process and immune process. In recent decades, cGAS-STING pathway, which can congenitally recognize exogenous and endogenous DNA for activation, has been widely reported to play critical roles in the innate immunity against some important diseases, such as infections and tumor. Manganese ion (Mn 2+ ) has been recently proved to specifically bind with cGAS and activate cGAS-STING pathway as a potential cGAS agonist, however, is significantly restricted by the low stability of Mn 2+ for further medical application. As one of the most stable forms of manganese, manganese dioxide (MnO 2 ) nanomaterials have been reported to show multiple promising functions, such as drug delivery, anti-tumor and anti-infection activities. More importantly, MnO 2 nanomaterials are also found to be a potential candidate as cGAS agonist by transforming into Mn 2+ , which indicates their potential for cGAS-STING regulations in different diseased conditions. In this review, we introduced the methods for the preparation of MnO 2 nanomaterials as well as their biological activities. Moreover, we emphatically introduced the cGAS-STING pathway and discussed the detailed mechanisms of MnO 2 nanomaterials for cGAS activation by converting into Mn 2+ . And we also discussed the application of MnO 2 nanomaterials for disease treatment by regulating cGAS-STING pathway, which might benefit the future development of novel cGAS-STING targeted treatments based on MnO 2 nanoplatforms., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Zhang, Hu, Zhang, Ruan, Ma, Chen, Huang, Fan, Lin, Huang, Liao, Lu, Xu, Pi and Guo.)

The LPP family is comprised of three enzymes that dephosphorylate bioactive lipid phosphates both intracellularly and extracellularly. Pre-clinical breast cancer models have demonstrated that decreased LPP1/3 with increased LPP2 expression correlates to tumorigenesis. This though has not been well verified in human specimens. In this study, we correlate LPP expression data to clinical outcomes in over 5000 breast cancers from three independent cohorts (TCGA, METABRIC, and GSE96058), investigate biological function using gene set enrichment analysis (GSEA) and the xCell cell-type enrichment analysis, and confirm sources of LPP production in the tumor microenvironment (TME) using single-cell RNA-sequencing (scRNAseq) data. Decreased LPP1/3 and increased LPP2 expression correlated to increased tumor grade, proliferation, and tumor mutational burden (all p < 0.001), as well as worse overall survival (hazard ratios 1.3-1.5). Further, cytolytic activity was decreased, consistent with immune system invasion. GSEA data demonstrated multiple increased inflammatory signaling, survival, stemness, and cell signaling pathways with this phenotype across all three cohorts. scRNAseq and the xCell algorithm demonstrated that most tumor LPP1/3 was expressed by endothelial cells and tumor-associated fibroblasts and LPP2 by cancer cells (all p < 0.01). Restoring the balance in LPP expression levels, particularly through LPP2 inhibition, could represent novel adjuvant therapeutic options in breast cancer treatment.

Advances in the management of Hodgkin lymphoma in children, adolescents and young adult have resulted in survival outcomes exceeding 90%. The risk of late toxicity, however, remains a significant concern for survivors of HL and the focus of modern trials have been to advance cure rates while reducing long term toxicity. This has been accomplished through response-adapted treatment approaches and the incorporation of novel agents, many of which target the unique interaction between the Hodgkin and Reed Sternberg cells and the tumor microenvironment. In addition, an improved understanding of prognostic markers, risk stratification, and the biology of this entity in children and AYAs may allow us to further tailor therapy. This review focuses on the current management of HL in the upfront and relapsed settings, recent advances in novel agents that target HL and the tumor microenvironment, and promising prognostic markers that may help guide the future management of HL., Competing Interests: Conflicts of interest The authors have no conflicts of interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Patients with metastatic or advanced pancreatic neuroendocrine tumors (NETs) carry poorer prognoses relative to patients with other NETs due to bulkier and often, more proliferative baseline disease. Patients with these tumors also possess more approved treatment options relative to patients with other NETs, making therapeutic sequencing nuanced. As such, defining optimal therapeutic sequencing and developing more potent cytoreductive treatments for patients are significant areas of research need in the field. Herein this review, we discuss the current systemic therapy landscape, our approach to therapeutic sequencing in the clinic and ongoing studies seeking to define optimal sequencing of systemic therapies, and novel therapeutics in development, for patients with pancreatic NETs. We limit the scope of this latter topic to agents with preclinical or clinical rationale over the last 8 years to provide a contemporary view of the drug development landscape and focus primarily on new types of peptide receptor radionuclide therapy, anti-vascular endothelial growth factor receptor tyrosine kinase inhibitors and anti-vascular endothelial growth receptor tyrosine kinase inhibitor plus immunotherapy combinations., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Predictive oncology, germline technologies, and adaptive seamless trials are promising advances in the treatment of lethal cancers. Yet, access to these therapies is stymied by costly research, regulatory barriers, and structural inequalities worsened by the COVID-19 pandemic., Methods: To address the need for a comprehensive strategy for rapid and more equitable access to breakthrough therapies for lethal cancers, we conducted a modified multi-round Delphi study with 70 experts in oncology, clinical trials, legal and regulatory processes, patient advocacy, ethics, drug development, and health policy in Canada, Europe, and the US. Semi-structured ethnographic interviews ( n  = 33) were used to identify issues and solutions that participants subsequently evaluated in a survey ( n  = 47). Survey and interview data were co-analyzed to refine topics for an in-person roundtable where recommendations for system change were deliberated and drafted by 26 participants., Results: Participants emphasized major issues in patient access to novel therapeutics including burdens of time, cost, and transportation required to complete eligibility requirements or to participate in trials. Only 12% of respondents reported satisfaction with current research systems, with "patient access to trials" and "delays in study approval" the topmost concerns., Conclusion: Experts agree that an equity-centered precision oncology communication model should be developed to improve access to adaptive seamless trials, eligibility reforms, and just-in-time trial activation. International advocacy groups are a key mobilizer of patient trust and should be involved at every stage of research and therapy approval. Our results also show that governments can promote better and faster access to life-saving therapeutics by engaging researchers and payors in an ecosystem approach that responds to the unique clinical, structural, temporal, and risk-benefit situations that patients with life-threatening cancers confront., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2023 Bright, Mills, Bradford and Stewart.)

Novel therapeutics to manage bacterial infections are urgently needed as the impact and prevalence of antimicrobial resistance (AMR) grows. Antivirulence therapeutics are an alternative approach to antibiotics that aim to attenuate virulence rather than target bacterial essential functions, while minimizing microbiota perturbation and the risk of AMR development. Beyond known virulence factors, pathogen-associated genes (PAGs; genes found only in pathogens to date) may play an important role in virulence or host association. Many identified PAGs encode uncharacterized hypothetical proteins and represent an untapped wealth of novel drug targets. Here, we review current advances in antivirulence drug research and development, including PAG identification, and provide a comprehensive workflow from the discovery of antivirulence drug targets to drug discovery. We highlight the importance of integrating bioinformatic/genomic-based methods for novel virulence factor discovery, coupled with experimental characterization, into existing drug screening platforms to develop novel and effective antivirulence drugs., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Heart diseases and related complications constitute a leading cause of death and socioeconomic threat worldwide. Despite intense efforts and research on the pathogenetic mechanisms of these diseases, the underlying cellular and molecular mechanisms are yet to be completely understood. Several lines of evidence indicate a critical role of inflammatory and oxidative stress responses in the development and progression of heart diseases. Nevertheless, the molecular machinery that drives cardiac inflammation and oxidative stress is not completely known. Recent data suggest an important role of cardiac bitter taste receptors (TAS2Rs) in the pathogenetic mechanism of heart diseases. Independent groups of researchers have demonstrated a central role of TAS2Rs in mediating inflammatory, oxidative stress responses, autophagy, impulse generation/propagation and contractile activities in the heart, suggesting that dysfunctional TAS2R signalling may predispose to cardiac inflammatory and oxidative stress disorders, characterised by contractile dysfunction and arrhythmia. Moreover, cardiac TAS2Rs act as gateway surveillance units that monitor and detect toxigenic or pathogenic molecules, including microbial components, and initiate responses that ultimately culminate in protection of the host against the aggression. Unfortunately, however, the molecular mechanisms that link TAS2R sensing of the cardiac milieu to inflammatory and oxidative stress responses are not clearly known. Therefore, we sought to review the possible role of TAS2R signalling in the pathophysiology of cardiac inflammation, oxidative stress, arrhythmia and contractile dysfunction in heart diseases. Potential therapeutic significance of targeting TAS2R or its downstream signalling molecules in cardiac inflammation, oxidative stress, arrhythmia and contractile dysfunction is also discussed., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The treatment of high-grade serous ovarian cancer and high-grade endometrioid ovarian cancer has seen significant improvements in recent years, with BRCA1/2 and homologous recombination status guiding a personalized approach which has resulted in improved patient outcomes. However, for other epithelial ovarian cancer subtypes, first-line treatment remains unchanged from the platinum-paclitaxel trials of the early 2000s. In this review, we explore novel therapeutic approaches being adopted in the treatment of clear cell, mucinous, carcinosarcoma and low-grade serous ovarian cancer and the biological rational behind them. We discuss why such disparities exist, the challenges faced in conducting dedicated trials in these rarer histologies and look towards new approaches being adopted to overcome them., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2023.)