Continuous evolving humanoid for advanced cellular models.

Preclinical Pharmacological Approaches in Drug Discovery for Chronic Pain.

Understanding features common to all forms of cancer is a vital component of treatment and research into malignant disease. All solid tumours share the ability to overcome contact inhibition of proliferation (CIP), the process by which intercellular contacts engage signalling to stop proliferation. Merlin, a tumour suppressor protein that is inactivated in a wide variety of cancers, plays a crucial role in CIP; merlin-deficient cells lose the ability to be contact-inhibited and subsequently form tumours. Although the role of merlin in cancer has been investigated extensively over the past 28 years, this protein has been notoriously difficult to study. To address this issue, we develop and utilize 2 split-luciferase biosensor systems that enable accurate quantification of merlin activity in real time. Merlin undergoes a conformational change that is functionally important in tumour suppression. Phosphorylation at a key C-terminal residue promotes transition of the protein from an open, active conformation to a closed, N-to-C terminal autoinhibited conformation. Therefore, monitoring this conformation change in real time could provide unique insights into merlin function. To do this, we apply NanoBiT split-luciferase technology to develop an intramolecular merlin biosensor (intra-Mer-BS). In brief, 2 split-luciferase components, LgBiT and SmBiT, are fused to the N- and C-terminus of merlin, respectively. Upon open-to-closed conformation change of merlin, LgBiT and SmBiT complement to reconstitute a functional luciferase and emit light. This enables accurate quantification of merlin’s functionally relevant conformation changes in real time. Importantly, cotransfection of the intra-Mer-BS alongside PAK1, an upstream merlin regulator that promotes transition to the closed conformation, significantly increases luminescent activity of the intra-Mer-BS, indicating that the biosensor faithfully reports on merlin’s conformation. Moreover, merlin has been shown to exert its tumour suppressive function through activation of LATS, the central mediator of the Hippo signalling pathway. In addition to the intra-Mer-BS, we develop and validate a NanoBiT biosensor to monitor the interaction between merlin and LATS (Mer-LATS-BS). This Mer-LATS-BS is used to quantify the effect of merlin activators and inhibitors on merlin/LATS tumour suppressive activity in cancer cells. In summary, we develop and validate 2 novel bioluminescent biosensors to monitor merlin’s conformation changes and activity in cancer cells. The intra-Mer-BS and Mer-LATS-BS provide real time information with high sensitivity and excellent reproducibility. Ultimately, these biosensors enable high throughput screening to discover novel upstream regulators of merlin in cancer and provide mechanistic insight into how contact inhibitive signalling is propagated through merlin and the Hippo pathway. Citation Format: Alexander J. Pipchuk, Xiaolong Yang. Development of ultrasensitive split luciferase biosensors monitoring activity of the merlin tumor suppressor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 858.

Background: Regenerative periodontal surgical therapy faces significant challenges due to the limited ability of the body to regenerate damaged periodontal tissue. One of the primary goals in regenerative periodontal therapy is regaining periodontal tissue attachment after destruction by periodontal disease. Currently, stem cells, harnessing three pivotal components—cells, biomaterials, and growth factors—are widely used in periodontal regeneration. Stem cells can be obtained from various sources, either by isolating cells from bone marrow, teeth, and muscles or through the somatic cell programming method (reprogramming) known as induced pluripotent stem cells (iPSCs). Purpose: This review aims to describe the potential use of iPSCs in the treatment of periodontal defects. Review: Search strategies were developed using the PubMed, LILACS, Scielo, and Wiley online databases during the period of 2012–2022. Ten articles met the inclusion criteria. iPSCs were obtained by inducing somatic cells from both dental and non-dental sources with factors Oct3/4, Sox2, Klf4, and c-Myc. Periodontal tissue regeneration procedures can be augmented with iPSCs. Unlike tooth-based stem cells, iPSCs offer several advantages, such as unlimited cell sources and the capability to differentiate into any cell type, including periodontal tissue. The potential of iPSCs extends to correcting periodontal bone defects and forming new periodontal tissues, such as alveolar bone, cementum, and periodontal ligament. However, iPSCs do have limitations, including the need for clinical trials, cell programming production facilities, and optimization of differentiated-cell functionality. Conclusion: The combined use of iPSCs in cell-based tissue engineering holds vast potential for future periodontal treatment strategies.

Patient-derived xenograft (PDX) models have gained attention due to their wide applications in basic research and drug development, and due to the increase in requirements for pathological analysis and anticancer drug evaluation. The development of immunodeficient mouse strains with high-level engraftment of normal and diseased cells has contributed to the considerable progress in understanding the human pathophysiology. The PDX model is one of the most important tools to bridge the gap between traditional animal models and the clinical trials. PDX not only recapitulates human disease in vivo, but also multiplies the tumor cells. Therefore, efforts were made internationally to develop a PDX bank for leukemias and solid tumors for future research and experimentation. PDX might be an ideal model to simulate actual human diseases for cancer research; however, some challenges still persist. Thus, this review aimed to summarize the developmental history of immune-deficient mice, the efforts of overcoming PDX limitations, PDX model applications for preclinical research, and the current attempts to establish domestic leukemia PDX bank in Japan.

The past decade has seen remarkable advances in the field of stem cell biology. Many new technologies and applications are passing the translational phase and likely will soon be relevant for the clinical pediatric cardiologist. This review will focus on two advances in basic science that are now translating into clinical trials. The first advance is the recognition, characterization, and recent therapeutic application of resident cardiac progenitor cells (CPCs). Early results of adult trials and scattered case reports in pediatric patients support expanding CPC-based trials for end-stage heart failure in pediatric patients. The relative abundance of CPCs in the neonate and young child offers greater potential benefits in heart failure treatment than has been realized to date. The second advance is the technology of induced pluripotent stem cells (iPSCs), which reprograms differentiated somatic cells to an undifferentiated embryonic-like state. When iPSCs are differentiated into cardiomyocytes, they model a patient's specific disease, test pharmaceuticals, and potentially provide an autologous source for cell-based therapy. The therapeutic recruitment and/or replacement of CPCs has potential for enhancing cardiac repair and regeneration in children with heart failure. Use of iPSCs to model heart disease holds great potential to gain new insights into diagnosis, pathophysiology, and disease-specific management for genetic-based cardiovascular diseases that are prevalent in pediatric patients.

Alzheimers Disease (AD) is a progressive and degenerative neurological disorder characterized by loss of cognition and memory. However, the pathogenesis of AD is still not clearly known. Current research in drug discovery for treatment of AD involves various targets, being only symptomatic, with the main therapeutic strategies based on "cholinergic hypothesis" and "amyloid cascade hypothesis". During the last decade, inhibitors of acetylcholinesterase (AChE) such as tacrine (Cognex®), donepezil (Aricept®), rivastigmine (Exelon®), and galanthamine (Reminyl®) have been launched. More recently, memantine (Ebixa®) has been emerged on the market as an N-methyl-D-aspartate (NMDA) receptor antagonist, which has been approved to be effective in the treatment of moderate to severe type of AD. In this review, we will focus on recent status of drug molecules for treatment of AD, currently either that in clinical practice, or still in clinical trials. Keywords: dementia, acetylcholinesterase inhibitor, NMDA receptor, Galanthamine, Amyloid cascade hypothesis, curcumin

Introduction In recent years, therapies that enhance anti cancer immune responses, like immune checkpoint inhibitors (ICIs), have transformed cancer treatment. Although these therapies can induce lasting responses across various cancer types, not all patients benefit from them. To maximize the potential of immuno oncology (IO) agents, researchers are exploring combinations with other treatments, such as radiotherapy, in both preclinical models and clinical trials. Understanding how IO therapies interact with radiotherapy to influence the tumor immune microenvironment (TIME), and other biomarkers is crucial for advancing drug discovery research. Methods and experimental procedures CT26 cells were exposed to various irradiation doses in vitro, and DNA damage response biomarkers were assessed using the Jess automated western blot system. Additionally, to establish a tolerated radiotherapy dosing regimen in vivo, different irradiation doses were tested in Balbc CT26 tumor bearing mice. The most effective and tolerated dose regimen was then combined with PD1 dosing. The response of the CT26 cancer model to PD1, with or without radiotherapy, was evaluated. Mice receiving radiotherapy were administered targeted X rays localized only to the tumor area. Changes to the tumor immune microenvironment (TIME) following these therapies were assessed using flow cytometry, while changes in splenic immune populations were analyzed by flow cytometry and ELISPOT. Serum cytokines at study termination were assessed using the Luminex x map technology. Data Treatment with radiotherapy or PD1 as monotherapies led to a mixed response, with tumor regressions obtained in a fraction of the animals treated. The combination of PD1 with radiotherapy significantly increased therapeutic efficacy. Characterizing the TIME following treatment with PD1 in combination with radiotherapy revealed modulation of the intra-tumoral immune infiltrate that reflected the increased therapeutic efficacy. Notably, a significant decrease in the frequency of tumor associated macrophages and an increase in T, NK, and B cells, was observed in tumors treated with the combination of anti PD1 and radiotherapy. Conclusion We have identified and established effective dosing regimens for radiotherapy in vivo in combination with PD1 therapy. Additionally, we have assessed changes to the tumor and spleen immune populations in a syngeneic mouse cancer model. These findings highlight the utility of these models in immuno-oncology (IO) drug discovery research. Citation Format: Charlotte Bell, Theoni (Tania) Katopodi, Pablo Binder, Tobias Bunday, Emily Wright, Amy Cantrell, Nick Moore, Stewart Brown, Paul Farrington, Shannon Sharman, Lyndsey Hanson, Lorraine Mooney, Jane Kendrew. Combining PD1 inhibition with radiotherapy enhances anti tumor responses in the CT26 colorectal mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2151.

Monumental evidence from clinical trials indicates an approximately 30% reduction in atheroslcerotic cardiovascular disease (ASCVD) risk using monotherapy with lipid-regulating drugs in dyslipidemic patients. In order to achieve greater reductions in risk, other approaches are necessary, including improvements in technology designed to assess ASCVD risk. Recent preliminary, but encouraging evidence indicates that by combining drugs that have different mechanisms of action on lipid metabolism yields not only an additive effect on the lipoprotein spectrum, but also reduces ASCVD events. New studies indicate that niacin potently increases high-density lipoproteins (HDL) by inhibiting HDL catabolism and decreases hepatic production of atherogenic very-low- and low-density lipoproteins by inhibiting the key enzyme for triglyceride synthesis (diacylglycerol acyltransferase). Statins, fibrates, bile acid sequestrants and ezetimibe have mechanisms that are different. Combination therapy using statins and niacin not only safely corrects dyslipidemia, but also yields ASCVD risk reduction significantly in excess of the 30% seen with monotherapy. Newer drugs with different mechanisms of action or combinations of new formulations have recently become available. Drug discovery research is likely to yield additional agents. Clinical trials focused on combination therapies to reduce ASCVD risk well beyond 30% need to be conducted to establish the rationale for further reducing the incidence of the primary cause of death today.

Bradykinin-from snake poison to therapeutic options.

Early identification of toxicity associated with new chemical entities (NCEs) is critical in preventing late-stage drug development attrition. Liver injury remains a leading cause of drug failures in clinical trials and post-approval withdrawals reflecting the poor translation between traditional preclinical animal models and human clinical outcomes. For this reason, preclinical strategies have evolved over recent years to incorporate more sophisticated human in vitro cell-based models with multi-parametric endpoints. This review aims to highlight the evolution of the strategies adopted to improve human hepatotoxicity prediction in drug discovery and compares/contrasts these with recent activities in our lab. The key role of human exposure and hepatic drug uptake transporters (e.g. OATPs, OAT2) is also elaborated.

Real-Time Monitoring Conformational Changes of a Intrinsically Disordered Protein with Aerolysin Nanopore

Introduction: Contract Research Organizations (CROs), Clinical Research Centers/Networks and private research institutions play an important role in the clinical research process, especially in the drug discovery and development process. They act as essential partners for pharmaceutical drug delivery/development and biotech companies. Over the last few decades, the demand for outsourcing of clinical research by pharmaceutical companies has increased, with the market for CRO and private research institutional services growing significantly. This trend has been driven by a need for increased productivity and efficiency to meet the increasing research and development costs, as well as the complexities associated with modern drug development. Statement of objective: This study has an objective to establish CROs with known recognition in sub Saharan Africa. Special emphasis on Cameroon institutions regulating and conduct clinical research. Methodology: Historically, drug discovery services were predominantly conducted in-house, safeguarding intellectual property and close collaboration with internal teams. However, the competitive nature of the sector has motivated pharmaceutical companies to adopt an outsourcing model, allowing them to decentralize, outsourced and exploit specialized expertise and technologies offered by the CROs. These partnerships enable drug developers to accelerate the identification and validation of promising drug candidates through streamlined pre-clinical and clinical trial processes. This is systematic research findings that we conducted a systematic search of the source documents from organizations, access to websites and google search to assemble our information, e-data information system. The systematic search gave us information on the contract organizations with online visibility. Vital information from annual reports, web information system management of the different organizations were accessible for easy navigations. Information on laws governing clinical research and major regulators in Cameroon. Results: Through a systematic online search contract research organization operating in Cameroon and Sub Saharan Africa that were available and accessible on line were identified. The list was not exhaustive as some CROs may be in existence but we could not have access to their activities and home page for enough visibility online. The organizations and CROs operating in Cameroon have been well illustrated. The laws and regulations governing clinical research in Cameroon has been well illustrated. It was observed that CROs face multiple challenges. The Contract Research Organization (CRO) are faced with multiple challenges that can be a limiting factor to their growth and quality service delivery: These challenges are listed though not exhaustive as Technological Disruption, Regulatory landscape, intellectual Property Issues, Economic Volatility, Limited Human resource expertise, Return on investment/High Costs: Conclusion/Recommendation: The CROs in Cameroon are required to be in compliance with the law regulating research in human subjects of 2022 and the regulations on Clinical research in Cameroon. In sub Saharan Africa CROs are aligned with the regulation enforced in their different countries. The success of CROs is based on their compliance to innovative trends in clinical research and the capacity to strengthen collaboration among policy makers and actors. The ability to face challenging opportunities in clinical research and embrace transformative breakthroughs that can bring faster new chemical entities to the market at the same time improving the standard of care (SOC) of the population. In the future, the synergy between innovation, strategic partnerships, and a commitment to excellence for CROs shall be the cornerstones of future success in conducting clinical research for Pharmaceutical drug discovery and development Based on the regulatory demanding nature of clinical regulation in Cameroon CROs must have a legal jurisdiction and recognition of their operation, and conform to the norms and standard laid down by regulatory authorities and the states of their jurisdiction CROs offer a wide range of services to support the development and execution of clinical trials, ensuring compliance with regulatory requirements and ethical standards. Clinical Research Organizations (CROs) play a pivotal role in the pharmaceutical, biotechnology, and medical device industries as a research service delivery provider on a contract basis.

A liver-on-a-chip platform with bioprinted hepatic spheroids

In the Policy Forum “To help aging populations, classify organismal senescence” (1 November 2019, p. [576][1]), S. R. G. Calimport et al. call for classification of senescence as a disease and propose a classification methodology. Unfortunately, their call to action comes a year after the publication of the 11th International Classification of Diseases (ICD) ([ 1 ][2]). The next revision of the ICD is expected in 2028 or later, and much progress needs to be made in basic research and clinical trials before including senescence would be possible. Calimport et al. 's assertion that aging-related diseases can be classified using current information overestimates our understanding of senescence. Multiple studies suggest that aging starts in utero ([ 2 ][3]) and staging of most senescence processes will require massive longitudinal studies in humans and animals. Furthermore, the first clinical trials targeting aging, such as Targeting Aging with Metformin (TAME), are under discussion, and no aging biomarker consensus or hierarchical structuring has yet emerged ([ 3 ][4], [ 4 ][5]). Staging senescence at the tissue-specific level for the purposes of preventative intervention may be a model for private or national health care plans and systems; however, these plans do not require these processes to be classified in the ICD with the individual codes. In addition to providing a general disease framework, ICD codes are used internationally to standardize burden of disease reports and assess cause of death. The concept of staging senescence does not fit the current ICD framework. The addition would likely require a new international initiative to develop a comprehensive set of biomarkers and interventions for senescence and longevity, as well as a set of recommendations for reducing the burden of senescence and aging-associated diseases. Pharmaceutical companies are already working on the interventions targeting the common biological pathways implicated in aging to deliver therapeutics against age-related diseases within the traditional health care paradigm. To accelerate drug development efforts focused on aging as a disease in the pharmaceutical industry, we need to demonstrate that basic research into whether aging is a biological process disease can yield valuable targets or interventions that demonstrate efficacy in treating or preventing age-related diseases. 1. [↵][6]1. A. Zhavoronkov, 2. B. Bhullar , Front. Genet. 6, 326 (2015). [OpenUrl][7] 2. [↵][8]1. B. J. Allison et al ., FASEB 30, 5 (2016). [OpenUrl][9] 3. [↵][10]1. J. N. Justice et al ., Cardiovasc. Endocrinol. Metab. 7, 80 (2018). [OpenUrl][11] 4. [↵][12]American Federation for Aging Research, “TAME trial” (2020); [www.afar.org/research/TAME/][13]. A.Z. is the founder and CEO of Insilico Medicine, a Hong Kong-based artificial intelligence company focused on drug discovery and aging research. He is also an adviser to Haut. AI Ltd., an Estonia-based artificial intelligence company focused on artificial intelligence for skin care and aging research. He is a director and co-founder of Deep Longevity, Inc., an artificial intelligence company focused on aging biomarkers. He is an adviser to the All Party Parliamentary Group (APPG) for Longevity in the UK. He is the seed investor in Retrotope, Inc., a California-based drug discovery company focused on age-related diseases. He may be associated with other startup companies in aging research as an adviser or through investments in Longenesis. [1]: http://www.sciencemag.org/content/366/6465/576 [2]: #ref-1 [3]: #ref-2 [4]: #ref-3 [5]: #ref-4 [6]: #xref-ref-1-1 View reference 1 in text [7]: {openurl}?query=rft.jtitle%253DFront.%2BGenet.%26rft.volume%253D6%26rft.spage%253D326%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [8]: #xref-ref-2-1 View reference 2 in text [9]: {openurl}?query=rft.jtitle%253DFASEB%26rft.volume%253D30%26rft.spage%253D5%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [10]: #xref-ref-3-1 View reference 3 in text [11]: {openurl}?query=rft.jtitle%253DCardiovasc.%2BEndocrinol.%2BMetab.%26rft.volume%253D7%26rft.spage%253D80%26rft.genre%253Darticle%26rft_val_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Ajournal%26ctx_ver%253DZ39.88-2004%26url_ver%253DZ39.88-2004%26url_ctx_fmt%253Dinfo%253Aofi%252Ffmt%253Akev%253Amtx%253Actx [12]: #xref-ref-4-1 View reference 4 in text [13]: http://www.afar.org/research/TAME/

The objective of the research is to investigate the role of very small embryonic-like stem cells (VSELs™), as well as CD34 + cells, in a study that will compare the efficacy of these two cell types for retinal repair.Licensing agreement: TiGenix & Sobi TiGenix (Belgium; www.tigenix.com)has licensed the marketing and distribution of ChondroCelect ® , the cell-based medicinal product for the repair of cartilage defects of the knee, to the international specialty healthcare company dedicated to rare diseases, Swedish Orphan Biovitrum AB (www.sobi.com).ChondroCelect was the first cellbased product to be approved in Europe.It is currently available for patients and reimbursed in Belgium, The Netherlands and Spain.Sales of ChondroCelect in 2013 were US$5.76 (EU€4.3)million, a growth of 25% on a like-for-like basis over 2012.Sobi will continue to market and distribute the product where it is currently available and has also acquired the exclusive rights to expand the product's availability to patients in multiple additional territories, including the rest of the EU, Norway, Switzerland, Turkey and Russia, plus the countries of the Middle East and North Africa.TiGenix will receive a royalty of 22% of the net sales of ChondroCelect in the first year of the agreement, and 20% of the net sales of ChondroCelect thereafter.There will be no upfront or milestone payments.The agreement took effect on June 1, 2014, and has a duration of 10 years. Launching new projects, products & servicesCatapult