Small Molecules For Treatment Research Articles

Urokinase-Type Plasminogen Activator Receptor (uPAR) in Inflammation and Disease: A Unique Inflammatory Pathway Activator

The urokinase-type plasminogen activator receptor (uPAR) is a unique protease binding receptor, now recognized as a key regulator of inflammation. Initially, uPA/uPAR was considered thrombolytic (clot-dissolving); however, recent studies have demonstrated its predominant immunomodulatory functions in inflammation and cancer. The uPA/uPAR complex has a multifaceted central role in both normal physiological and also pathological responses. uPAR is expressed as a glycophosphatidylinositol (GPI)-linked receptor interacting with vitronectin, integrins, G protein-coupled receptors, and growth factor receptors within a large lipid raft. Through protein-to-protein interactions, cell surface uPAR modulates intracellular signaling, altering cellular adhesion and migration. The uPA/uPAR also modifies extracellular activity, activating plasminogen to form plasmin, which breaks down fibrin, dissolving clots and activating matrix metalloproteinases that lyse connective tissue, allowing immune and cancer cell invasion and releasing growth factors. uPAR is now recognized as a biomarker for inflammatory diseases and cancer; uPAR and soluble uPAR fragments (suPAR) are increased in viral sepsis (COVID-19), inflammatory bowel disease, and metastasis. Here, we provide a comprehensive overview of the structure, function, and current studies examining uPAR and suPAR as diagnostic markers and therapeutic targets. Understanding uPAR is central to developing diagnostic markers and the ongoing development of antibody, small-molecule, nanogel, and virus-derived immune-modulating treatments that target uPAR.

Lipid-Based Nanocarriers for Targeted Gene Delivery in Lung Cancer Therapy: Exploring a Novel Therapeutic Paradigm.

Lung cancer is a significant cause of cancer-related death worldwide. It can be broadly categorised into small-cell lung cancer (SCLC) and Non-small cell lung cancer (NSCLC). Surgical intervention, radiation therapy, and the administration of chemotherapeutic medications are among the current treatment modalities. However, the application of chemotherapy may be limited in more advanced stages of metastasis due to the potential for adverse effects and a lack of cell selectivity. Although small-molecule anticancer treatments have demonstrated effectiveness, they still face several challenges. The challenges at hand in this context comprise insufficient solubility in water, limited bioavailability at specific sites, adverse effects, and the requirement for epidermal growth factor receptor inhibitors that are genetically tailored. Bio-macromolecular drugs, including small interfering RNA (siRNA) and messenger RNA (mRNA), are susceptible to degradation when exposed to the bodily fluids of humans, which can reduce stability and concentration. In this context, nanoscale delivery technologies are utilised. These agents offer encouraging prospects for the preservation and regulation of pharmaceutical substances, in addition to improving the solubility and stability of medications. Nanocarrier-based systems possess the notable advantage of facilitating accurate and sustained drug release, as opposed to traditional systemic methodologies. The primary focus of scientific investigation has been to augment the therapeutic efficacy of nanoparticles composed of lipids. Numerous nanoscale drug delivery techniques have been implemented to treat various respiratory ailments, such as lung cancer. These technologies have exhibited the potential to mitigate the limitations associated with conventional therapy. As an illustration, applying nanocarriers may enhance the solubility of small-molecule anticancer drugs and prevent the degradation of bio-macromolecular drugs. Furthermore, these devices can administer medications in a controlled and extended fashion, thereby augmenting the therapeutic intervention's effectiveness and reducing adverse reactions. However, despite these promising results, challenges remain that must be addressed. Multiple factors necessitate consideration when contemplating the application of nanoparticles in medical interventions. To begin with, the advancement of more efficient delivery methods is imperative. In addition, a comprehensive investigation into the potential toxicity of nanoparticles is required. Finally, additional research is needed to comprehend these treatments' enduring ramifications. Despite these challenges, the field of nanomedicine demonstrates considerable promise in enhancing the therapy of lung cancer and other respiratory diseases.

Cost-Effectiveness Analysis of Innovative Therapies for Patients with Non-Alcoholic Fatty Liver Disease.

Currently there are no disease-specific approved therapies for non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH); however, several treatments are under development. This study aimed to estimate the cost-effectiveness of hypothetical innovative therapies compared with lifestyle intervention alone and combined with pioglitazone, and assess the health economic consequences of their future availability for patients. A Markov cohort model was developed, considering fourteen disease health states and one absorbing state representing death. Transition probabilities, costs, utilities, and treatment efficacy were based on published data and assumptions. Four treatment strategies were considered, including two existing therapies (lifestyle intervention, small molecule treatment) and two hypothetical interventions (biological and curative therapy). The analysis was performed from the US third-party payer perspective. The curative treatment with the assumed efficacy of 70% of patients cured and assumed price of $500,000 was the only cost-effective option. Although it incurred higher costs (a difference of $188,771 vs. lifestyle intervention and $197,702 vs. small molecule), it generated more QALYs (a difference of 1.58 and 1.38 QALYs, respectively), resulting in an ICER below the willingness-to-pay threshold of $150,000 per QALY. The sensitivity analyses showed that the results were robust to variations in model parameters. This study highlighted the potential benefits of therapies aimed at curing a disease rather than stopping its progression. Nonetheless, each of the analyzed therapies could be cost-effective compared with lifestyle intervention at a relatively high price.

Notoginsenoside Ft1 inhibits colorectal cancer growth by increasing CD8+ T cell proportion in tumor-bearing mice through the USP9X signaling pathway

The management of colorectal cancer (CRC) poses a significant challenge, necessitating the development of innovative and effective therapeutics. Our research has shown that notoginsenoside Ft1 (Ng-Ft1), a small molecule, markedly inhibits subcutaneous tumor formation in CRC and enhances the proportion of CD8+ T cells in tumor-bearing mice, thus restraining tumor growth. Investigation into the mechanism revealed that Ng-Ft1 selectively targets the deubiquitination enzyme USP9X, undermining its role in shielding β-catenin. This leads to a reduction in the expression of downstream effectors in the Wnt signaling pathway. These findings indicate that Ng-Ft1 could be a promising small-molecule treatment for CRC, working by blocking tumor progression via the Wnt signaling pathway and augmenting CD8+ T cell prevalence within the tumor environment.

Targeted-Neuroinflammation Mitigation Using Inflammasome-Inhibiting Nanoligomers is Therapeutic in an Experimental Autoimmune Encephalomyelitis Mouse Model.

Multiple sclerosis (MS) is a debilitating autoimmune disease that impacts millions of patients worldwide, disproportionately impacting women (4:1), and often presenting at highly productive stages of life. This disease affects the spinal cord and brain and is characterized by severe neuroinflammation, demyelination, and subsequent neuronal damage, resulting in symptoms like loss of mobility. While untargeted and pan-immunosuppressive therapies have proven to be disease-modifying and manage (or prolong the time between) symptoms in many patients, a significant fraction are unable to achieve remission. Recent work has suggested that targeted neuroinflammation mitigation through selective inflammasome inhibition can offer relief to patients while preserving key components of immune function. Here, we show a screening of potential therapeutic targets using inflammasome-inhibiting Nanoligomers (NF-κB1, TNFR1, TNF-α, IL-6) that meet or far-exceed commercially available small-molecule counterparts like ruxolitinib, MCC950, and deucravacitinib. Using the human brain organoid model, top Nanoligomer combinations (NF-κB1 + TNFR1: NI111, and NF-κB1 + NLRP3: NI112) were shown to significantly reduce neuroinflammation without any observable negative impact on organoid function. Further testing of these top Nanoligomer combinations in an aggressive experimental autoimmune encephalomyelitis (EAE) mouse model for MS using intraperitoneal (IP) injections showed that NF-κB1 and NLRP3 targeting Nanoligomer combination NI112 rescues mice without observable loss of mobility or disability, minimal inflammation in brain and spinal cord histology, and minimal to no immune cell infiltration of the spinal cord and no demyelination, similar to or at par with mice that received no EAE injections (negative control). Mice receiving NI111 (NF-κB1 + TNFR1) also showed reduced neuroinflammation compared to saline (sham)-treated EAE mice and at par/similar to other inflammasome-inhibiting small molecule treatments, although it was significantly higher than NI112 leading to subsequent worsening clinical outcomes. Furthermore, treatment with an oral formulation of NI112 at lower doses showed a significant reduction in EAE severity, albeit with higher variance owing to administration and formulation/fill-and-finish variability. Overall, these results point to the potential of further development and testing of these inflammasome-targeting Nanoliogmers as an effective neuroinflammation treatment for multiple neurodegenerative diseases and potentially benefit several patients suffering from such debilitating autoimmune diseases like MS.

Pediatric inflammatory bowel disease: What’s new and what has changed?

Abstract The incidence and prevalence of inflammatory bowel disease (IBD) is on the rise in North America and worldwide, with young children being the fastest growing patient population. It is therefore essential for pediatricians and pediatric sub-specialists to be able to recognize signs and symptoms suspicious for a new diagnosis of IBD, as well as potential complications associated with IBD or its treatment. This article reviews the most recent literature regarding clinical presentation, helpful diagnostic clues, newer monitoring tools being used by pediatric gastroenterologists, and emerging new biologic and small molecule treatments.

Biologics in Focus: A Comprehensive Review of the Current Biological Therapies for Ulcerative Colitis in the United Arab Emirates (UAE)

Background: Ulcerative colitis (UC) is a relapsing–remitting inflammatory condition that has an increasing incidence across the world, including in the Middle East. Biological monoclonal antibody drugs (biologics) have been shown to be advantageous in treating UC. We undertook a review of the currently available biological and small-molecule therapies, with a particular emphasis on those currently licensed in the United Arab Emirates (UAE). Methods: We conducted a literature search for studies on biological therapies using the PubMed, MEDLINE, and Embase databases using a list of keywords that were generated following referral to existing treatment guidelines for UC. Papers looking at biological and small-molecule treatments for UC in adult populations were included. Pediatric, pregnancy, and cost-effectiveness studies were excluded. Results and Discussion: There are currently three classes of biologics (anti-tumor necrosis factors (anti-TNFs), anti-integrins, and anti-interleukins) and one class of small-molecule therapy (Janus kinase (JAK) inhibitor) licensed for UC treatment in the UAE. Within the anti-TNF class, three medications have been approved: infliximab, adalimumab, and golimumab. For JAK inhibitors, there are two: tofacitinib and upadacitinib. There is only one licensed medication in the remaining classes: vedolizumab (anti-integrin) and ustekinumab (anti-interleukin). The length of studies varied from 6–8 weeks for induction studies and 52 weeks for maintenance studies. The studies demonstrated increased efficacy in these medications compared to placebos when clinical response, clinical remission, and other secondary measures such as mucosal healing were assessed following the induction and maintenance phases. Biosimilars of infliximab and adalimumab are also available for treating UC, and their safety and efficacy were compared to their biologic originators. Conclusions: The introduction of biologics has been proven to be beneficial for the treatment of UC. This review summarizes the efficacy and safety of each biological class in the treatment of the disease; however, biological drug registries and further studies are required to offer more insight into the comparative efficacy and safety of these agents.

S100A8/A9 predicts response to PIM kinase and PD-1/PD-L1 inhibition in triple-negative breast cancer mouse models

BackgroundUnderstanding why some triple-negative breast cancer (TNBC) patients respond poorly to existing therapies while others respond well remains a challenge. This study aims to understand the potential underlying mechanisms distinguishing early-stage TNBC tumors that respond to clinical intervention from non-responders, as well as to identify clinically viable therapeutic strategies, specifically for TNBC patients who may not benefit from existing therapies.MethodsWe conducted retrospective bioinformatics analysis of historical gene expression datasets to identify a group of genes whose expression levels in early-stage tumors predict poor clinical outcomes in TNBC. In vitro small-molecule screening, genetic manipulation, and drug treatment in syngeneic mouse models of TNBC were utilized to investigate potential therapeutic strategies and elucidate mechanisms of drug action.ResultsOur bioinformatics analysis reveals a robust association between increased expression of immunosuppressive cytokine S100A8/A9 in early-stage tumors and subsequent disease progression in TNBC. A targeted small-molecule screen identifies PIM kinase inhibitors as capable of decreasing S100A8/A9 expression in multiple cell types, including TNBC and immunosuppressive myeloid cells. Combining PIM inhibition and immune checkpoint blockade induces significant antitumor responses, especially in otherwise resistant S100A8/A9-high PD-1/PD-L1-positive tumors. Notably, serum S100A8/A9 levels mirror those of tumor S100A8/A9 in a syngeneic mouse model of TNBC.ConclusionsOur data propose S100A8/A9 as a potential predictive and pharmacodynamic biomarker in clinical trials evaluating combination therapy targeting PIM and immune checkpoints in TNBC. This work encourages the development of S100A8/A9-based liquid biopsy tests for treatment guidance.

New and Emerging Oral/Topical Small-Molecule Treatments for Psoriasis.

The introduction of biologic therapies has led to dramatic improvements in the management of moderate-to-severe psoriasis. Even though the efficacy and safety of the newer biologic agents are difficult to match, oral administration is considered an important advantage by many patients. Current research is focused on the development of oral therapies with improved efficacy and safety compared with available alternatives, as exemplified by deucravacitinib, the first oral allosteric Tyk2 inhibitor approved for the treatment of moderate to severe psoriasis in adults. Recent advances in our knowledge of psoriasis pathogenesis have also led to the development of targeted topical molecules, mostly focused on intracellular signaling pathways such as AhR, PDE-4, and Jak-STAT. Tapinarof (an AhR modulator) and roflumilast (a PDE-4 inhibitor) have exhibited favorable efficacy and safety outcomes and have been approved by the FDA for the topical treatment of plaque psoriasis. This revision focuses on the most recent oral and topical therapies available for psoriasis, especially those that are currently under evaluation and development for the treatment of psoriasis.

Iron-triggered signaling via ETS1 and the p38/JNK MAPK pathway regulates Bmp6 expression.

BMP6 is an iron-sensing cytokine whose transcription in liver sinusoidal endothelial cells (LSECs) is enhanced by high iron levels, a step that precedes the induction of the iron-regulatory hormone hepcidin. While several reports suggested a cell-autonomous induction of Bmp6 by iron-triggered signals, likely via sensing of oxidative stress by the transcription factor NRF2, other studies proposed the dominant role of a paracrine yet unidentified signal released by iron-loaded hepatocytes. To further explore the mechanisms of Bmp6 transcriptional regulation, we used female mice aged 10-11 months, which are characterized by hepatocytic but not LSEC iron accumulation, and no evidence of systemic iron overload. We found that LSECs of aged mice exhibit increased Bmp6 mRNA levels as compared to young controls, but do not show a transcriptional signature characteristic of activated NFR2-mediated signaling in FACS-sorted LSECs. We further observed that primary murine LSECs derived from both wild-type and NRF2 knock-out mice induce Bmp6 expression in response to iron exposure. By analyzing transcriptomic data of FACS-sorted LSECs from aged versus young mice, as well as early after iron citrate injections, we identified ETS1 as a candidate transcription factor involved in Bmp6 transcriptional regulation. By performing siRNA-mediated knockdown, small-molecule treatments, and chromatin immunoprecipitation in primary LSECs, we show that Bmp6 transcription is regulated by iron via ETS1 and p38/JNK MAP kinase-mediated signaling, at least in part independently of NRF2. Thereby, these findings identify the new components of LSEC iron sensing machinery broadly associated with cellular stress responses.

SYSTEMATIC REVIEW WITH META-ANALYSIS: SAFETY AND EFFICTIVENESS OF COMBINING BIOLOGICS AND SMALL MOLECULES IN INFLMAMMATORY BOWEL DISEASE

Abstract BACKGROUND Effectiveness and safety of Dual biologic therapy (DBT) or in combination with small molecules for treatment of refractory cases of inflammatory bowel diseases (IBD) has been studied previously. In this systematic review and meta-analysis (SRMA), our aim was to update prior SRMA by Alayo et al including newer studies and randomized clinical trials Explorer and VEGA and newer endpoints including corticosteroid free remission rates, need for surgeries, and effectiveness based on IBD subtype. METHODS We conducted a systematic literature search using Clinical trials.gov, Cochrane Library, Embase, Ovid Medline, PubMed Medline, Scopus and Web of Science, identifying additional relevant studies published until January 19, 2023. Random-effects inverse variance model was used to combine the proportions of patients who achieved response/remission or developed AEs to obtain pooled estimates (primary outcomes). RESULTS A total of 1184 citations were identified through the database searches, of which 360 duplicates and 755 unsuitable studies were excluded following title/abstract screening. Then, the full-texts of the remaining 69 articles were retrieved for further investigation. Of these, 59 were excluded, leaving 10 additional eligible studies since the prior systematic review. A total of 23 studies met the inclusion criteria including 13 in prior SRMA, published between 2007 and 2023. Final analysis included 531 patients who underwent 543 therapeutic trials (TTs) of 8 different combination therapies. Of these 264 (49.7%) were men men. Among combination therapies, Ustekinumab (UST) + anti-tumor necrosis factor-alpha antagonist (aTNF) had the highest pooled clinical response (81.6% [95% CI: 66.2-97.0], I2=52%, p=0.04; 9 studies, 44 TTs) and remission (Figure 1) (64.2% [95% CI: 45.2-83.1], I2=55%, p=0.03; 8 studies, 42 TTs) rates. In patients with CD, the highest pooled clinical response and remission rates pertained to UST + aTNF (91.6% [95% CI: 79.8-100.0], I2 = 19%, p=0.28; 8 studies, 29 TTs). In patients with UC, the highest pooled clinical response rate was seen with Vedolizumab (VDZ)+UST (100.0% [95% CI: 70.0-100.0], I2 = 0%, p=1.00; 4 studies, 4 TTs) and UST + aTNF (100.0% [95% CI: 73.2-100.0], I2 = 0%, p =1.00; 4 studies, 5 TTs). and while the highest pooled clinical remission rate was with VDZ + UST (75.0% [95% CI: 26.0-100.0], I2 = 63%, p=0.05; 4 studies, 4 TTs). The lowest pooled AEs rate (Figure 2) related to tofacitinib (Tofa) + VDZ (12.5% [95% CI: 2.9-22.0], I2 = 41%, p = 0.10; 8 studies, 76 TTs), followed by UST + aTNF (12.7% [95% CI: 0.0-25.8], I2=43%, p = 0.08; 9 studies, 43 TTs) and Tofa+aTNF (13.0% [95% CI: 0.8-25.3], I2=49%, p=0.08; 6 studies, 27 TTs) in patients with IBD. CONCLUSION Combining biologics or with small molecules in treatment of refractory IBD is promising and appeared to be generally safe with no major side effects. Figure 1 Clinical remission Figure 2 Adverse events

Combined small-molecule treatment accelerates maturation of human pluripotent stem cell-derived neurons.

The maturation of human pluripotent stem cell (hPSC)-derived neurons mimics the protracted timing of human brain development, extending over months to years for reaching adult-like function. Prolonged in vitro maturation presents a major challenge to stem cell-based applications in modeling and treating neurological disease. Therefore, we designed a high-content imaging assay based on morphological and functional readouts in hPSC-derived cortical neurons which identified multiple compounds that drive neuronal maturation including inhibitors of lysine-specific demethylase 1 and disruptor of telomerase-like 1 and activators of calcium-dependent transcription. A cocktail of four factors, GSK2879552, EPZ-5676, N-methyl-D-aspartate and Bay K 8644, collectively termed GENtoniK, triggered maturation across all parameters tested, including synaptic density, electrophysiology and transcriptomics. Maturation effects were further validated in cortical organoids, spinal motoneurons and non-neural lineages including melanocytes and pancreatic β-cells. The effects on maturation observed across a broad range of hPSC-derived cell types indicate that some of the mechanisms controlling the timing of human maturation might be shared across lineages.

Abstract A125: Clinical evaluation of a functional combinatorial precision medicine platform to predict combination immunotherapy responses in hematological malignancies

Abstract Purpose: Proliferation of immune checkpoint inhibitors and lineage-specific antigen-based therapy have made identifying the most appropriate immunotherapy for specific patients or subgroups of patients increasingly difficult. Furthermore, combination of these therapeutic antibodies with other targeted agents or chemotherapy is often required to achieve durable response. To address the large search space of possible combinations of these immunotherapies with available targeted and cytotoxic drug partners, we applied a hybrid experimental-analytical platform, Flow Cytometry Immunophenotyping–Quadratic Phenotypic Optimization Platform (FCI-QPOP), on primary patient samples from acute myeloid leukemia (AML) and multiple myeloma (MM) cases to predict patient and subtype-specific combination immunotherapy responses. Successful development of this functional combinatorial precision medicine platform could help guide combination therapy treatment while also providing a tool for improving combination therapy design for emerging immunotherapies. Experimental Detail: Single drug dosage response analysis of a set of immunotherapies, targeted small molecules and cytotoxic agents were performed from initial patient samples and used to inform subsequent dosing levels for 8-drug, 3-level FCI-QPOP. In FCI-QPOP, primary AML or MM patient samples composed of both cancer cells and normal cells were treated with an array of test combinations and analyzed by flow cytometry to provide a quantitative phenotypic output for each test combination. This OACD dataset was then analyzed by QPOP to rank all possible drug combinations towards a predicted treatment outcome. Concordance analysis was then performed comparing patient sample results with parallel treatment initiated at time of sample collection. Results: Drug-dose response analysis by flow cytometry could accurately identify samples-specific response, including IC50 determination, to both therapeutic antibodies and small molecule drugs. Following this, 8-drug, 3-level FCI-QPOP was successfully performed on 14 of 17 primary patient samples. Concordance analysis could be performed on 9 cases, with 5 cases still pending clinical follow-up. Concordance to both antibody therapies as well as small molecule treatments were analyzed following FCI-QPOP. FCI-QPOP had a sensitivity of 80% and specificity of 75% and a total predictive value (TPV) of 77.78%. Additionally, FCI-QPOP provided potentially effective combination rankings for a diverse range of therapeutic antibodies, including gemtuzumab-based combination therapies. Conclusion: The results show the potential for FCI-QPOP to predict clinical response to immunotherapy-based treatments. Furthermore, FCI-QPOP can improve drug development pipelines through patient samples-based design of effective immunotherapy-based combinations that may benefit larger populations of patients or specific subgroups of patients. Citation Format: Noor Rashidha Bte Meera Sahib, Masturah Rashid, Sanjay de Mel, Wei Ying Jen, Melissa Ooi, Edward K Chow. Clinical evaluation of a functional combinatorial precision medicine platform to predict combination immunotherapy responses in hematological malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A125.

Long term follow-up of refractory/relapsed hairy cell leukaemia patients treated with low-dose vemurafenib between 2013 and 2022 at the Department of Internal Medicine and Oncology, Semmelweis University.

Introduction: Hairy cell leukemia (HCL) is an indolent B-cell lymphoproliferative disease. BRAF V600E mutation is detected in nearly all classical HCL cases which offers the possibility of targeted therapy. Objective: The aim of our study was to assess the efficacy of low-dose vemurafenib as well as to assess the long term outcome of HCL patients treated with this drug at the Department of Internal Medicine and Oncology at Semmelweis University. Methods: We report on 10 patients with classical HCL treated with low-dose vemurafenib at our Department between 2013 and 2022. Results: As a result of fixed time low-dose vemurafenib treatment, 5 of 10 patients (5/10) achieved partial remission, 4 (4/10) had stable disease, and 1 (1/10) had MRD positivity. No patients achieved complete remission. The median progression-free survival was 28.5months while the overall survival was 82months. Conclusion: We confirm that low dose of vemurafenib is effective and safe in the vast majority of patients with HCL. This small-molecule oral treatment allows to gain valuable time-months or even years-before further, usually parenteral treatment options have to be given or before previous treatment has to be repeated. There are also promising data supporting the combination of vemurafenib with other drugs for the treatment of HCL patients which could provide even further possibility to bridge treatment.

Risk of Cancer Recurrence in Patients With Immune-Mediated Diseases With Use of Immunosuppressive Therapies: An Updated Systematic Review and Meta-Analysis

There are limited data on the safety of immunosuppressive therapy use in individuals with immune-mediated diseases with a history of malignancy, particularly with newer biologic and small-molecule treatments. We performed a systematic search of PubMed and Embase databases to identify studies examining the impact of immunosuppressive therapies on cancer recurrence across several immune-mediated diseases. Studies were pooled together using random-effects meta-analysis and stratified by type of treatment. Primary outcome was occurrence of incident cancers, defined as new or recurrent. Our meta-analysis included 31 studies (17 inflammatory bowel disease, 14 rheumatoid arthritis, 2 psoriasis, and 1 ankylosing spondylitis) contributing 24,328 persons and 85,784 person-years (p-y) of follow-up evaluation. Rates of cancer recurrence were similar among individuals not on immunosuppression (IS) (1627 incident cancers, 43,765 p-y; 35 per 1000 p-y; 95% CI, 27-43), receiving an anti-tumor necrosis factor (571 incident cancers, 17,772 p-y; 32 per 1000 p-y; 95% CI, 25-38), immunomodulators (1104 incident cancers, 17,018 p-y; 46 per 1000 p-y; 95% CI, 31-61), combination immunosuppression (179 incident cancers, 2659 p-y; 56 per 1000 p-y; 95% CI, 31-81). Patients receiving ustekinumab (5 incident cancers, 213 p-y; 21 per 1000 p-y; 95% CI, 0-44) and vedolizumab (37 incident cancers, 1951 p-y; 16 per 1000 p-y; 95% CI, 5-26) had numerically lower rates of cancer. There were no studies on Janus kinase inhibitors. Stratification of studies by timing of immunosuppression initiation did not reveal a medication effect based on early (<5 years) or delayed treatment initiation. In patients with immune-mediated diseases and a history of malignancy, we observed similar rates of cancer recurrence in those on no immunosuppression compared with different immunosuppressive treatments.

Regenerative engineering of long bones using the small molecule forskolin

Bone grafting procedures have become increasingly common in the United States, with approximately 500,000 cases occurring each year at a societal cost exceeding $2.4 billion. Recombinant human bone morphogenetic proteins (rhBMPs) are therapeutic agents that have been widely used by orthopedic surgeons to stimulate bone tissue formation alone and when paired with biomaterials. However, significant limitations such as immunogenicity, high production cost, and ectopic bone growth from these therapies remain. Therefore, efforts have been made to discover and repurpose osteoinductive small-molecule therapeutics to promote bone regeneration. Previously, we have demonstrated that a single-dose treatment with the small-molecule forskolin for just 24 h induces osteogenic differentiation of rabbit bone marrow-derived stem cells invitro, while mitigating adverse side effects attributed with prolonged small-molecule treatment schemes. In this study, we engineered a composite fibrin-PLGA [poly(lactide-co-glycolide)]-sintered microsphere scaffold for the localized, short-term delivery of the osteoinductive small molecule, forskolin. Invitro characterization studies showed that forskolin released out of the fibrin gel within the first 24 h and retained its bioactivity toward osteogenic differentiation of bone marrow-derived stem cells. The forskolin-loaded fibrin-PLGA scaffold was also able to guide bone formation in a 3-mo rabbit radial critical-sized defect model comparable to recombinant human bone morphogenetic protein-2 (rhBMP-2) treatment, as demonstrated through histological and mechanical evaluation, with minimal systemic off-target side effects. Together, these results demonstrate the successful application of an innovative small-molecule treatment approach within long bone critical-sized defects.

A modified natural small molecule inhibits triple-negative breast cancer growth by interacting with Tubb3

BackgroundTriple-negative breast cancer (TNBC) is a malignant tumor without specific therapeutic targets and a poor prognosis. Chemotherapy is currently the first-line therapeutic option for TNBC. However, due to the heterogeneity of TNBC, not all of TNBC patients are responsive to chemotherapeutic agents. Therefore, the demand for new targeted agents is critical. β-tubulin isotype III (Tubb3) is a prognostic factor associated with cancer progression, including breast cancer, and targeting Tubb3 may lead to improve TNBC disease control. Shikonin, the active compound in the roots of Lithospermun erythrorhizon suppresses the growth of various types of tumors, and its efficacy can be improved by altering its chemical structure. PurposeIn this work, the anti-TNBC effect of a shikonin derivative (PMMB276) was investigated, and its mechanism was also investigated. Study Design/MethodsThis study combines flow cytometry, immunofluorescence staining, immunoblotting, immunoprecipitation, siRNA silencing, and the iTRAQ proteomics assay to analyze the inhibition potential of PMMB276 on TNBC. In vivo study was performed, Balb/c female murine models with or without the small molecule treatments. ResultsHerein, we screened 300 in-house synthesized analogs of shikonin against TNBC and identified a novel small molecule, PMMB276; it suppressed cell proliferation, induced apoptosis, and arrested the cell cycle at the G2/M phase, suggesting that it could have a tumor suppressive role in TNBC. Tubb3 was identified as the target of PMMB276 using proteomic and biological activity analyses. Meanwhile, PMMB276 regulated microtubule dynamics in vitro by inducing microtubule depolymerization and it could act as a tubulin stabilizer by a different process than that of paclitaxel. Moreover, suppressing or inhibiting Tubb3 with PMMB276 reduced the growth of breast cancer in an experimental mouse model, indicating that Tubb3 plays a significant role in TNBC progression. ConclusionThe findings support the therapeutic potential of PMMB276, a Tubb3 inhibitor, as a treatment for TNBC. Our findings might serve as a foundation for the utilization of shikonin and its derivatives in the development of anti-TNBC.

Computational approaches streamlining drug discovery.

Computer-aided drug discovery has been around for decades, although the past few years have seen a tectonic shift towards embracing computational technologies in both academia and pharma. This shift is largely defined by the flood of data on ligand properties and binding to therapeutic targets and their 3D structures, abundant computing capacities and the advent of on-demand virtual libraries of drug-like small molecules in their billions. Taking full advantage of these resources requires fast computational methods for effective ligand screening. This includes structure-based virtual screening of gigascale chemical spaces, further facilitated by fast iterative screening approaches. Highly synergistic are developments in deep learning predictions of ligand properties and target activities in lieu of receptor structure. Here we review recent advances in ligand discovery technologies, their potential for reshaping the whole process of drug discovery and development, as well as the challenges they encounter. We also discuss how the rapid identification of highly diverse, potent, target-selective and drug-like ligands to protein targets can democratize the drug discovery process, presenting new opportunities for the cost-effective development of safer and more effective small-molecule treatments.

GSK will license Scynexis antifungal

GSK is beefing up its infectious disease portfolio with an antifungal from Scynexis. For $90 million up front and possible milestone-based payments up to $503 million, the pharma giant will get the rights to commercialize and further develop Scynexis’s antifungal Brexafemme (ibrexafungerp). The small-molecule treatment is approved by the US Food and Drug Administration to treat vulvovaginal candidiasis (VVC) and to reduce the incidence of recurrent VVC. It’s the first and only oral antifungal approved for both indications, according to the firms. Notably, the companies say ibrexafungerp has also shown activity against Candida auris , which is currently spreading through US health-care facilities. C. auris has been responsible for severe illness in people who are hospitalized, and it is frequently resistant to multiple commonly used antifungals, the US Centers for Disease Control and Prevention says . Ibrexafungerp is also in Phase 3 trials to treat invasive candidiasis , which is

Comparison of Pronase versus Manual Dechorionation of Zebrafish Embryos for Small Molecule Treatments.

Zebrafish are a powerful animal model for small molecule screening. Small molecule treatments of zebrafish embryos usually require that the chorion, an acellular envelope enclosing the embryo, is removed in order for chemical compounds to access the embryo from the bath medium. For large-scale studies requiring hundreds of embryos, manual dechorionation, using forceps, can be a time-consuming and limiting process. Pronase is a non-specific protease that is widely used as an enzymatic alternative for dechorionating zebrafish embryos. However, whether pronase treatments alter the effects of subsequent small molecule treatments has not been addressed. Here, we provide a detailed protocol for large-scale pronase dechorionation of zebrafish embryos. We tested whether pronase treatment can influence the efficacy of drug treatments in zebrafish embryos. We used a zebrafish model for Duchenne muscular dystrophy (DMD) to investigate whether the efficacies of trichostatin-A (TSA) or salermide + oxamflatin, small molecule inhibitors known to ameliorate the zebrafish dmd muscle degeneration phenotype, are significantly altered when embryos are treated with pronase versus manual dechorionation. We also tested the effects of pronase on the ability of the anthracycline cancer drug doxorubicin to induce cardiotoxicity in zebrafish embryos. When comparing pronase- versus forceps-dechorionated embryos used in these small molecule treatments, we found no appreciable effects of pronase on animal survival or on the effects of the small molecules. The significant difference that was detected was a small improvement in the ability of salermide + oxamflatin to ameliorate the dmd phenotype in pronase-treated embryos when compared with manual dechorionation. Our study supports the use of pronase treatment as a dechorionation method for zebrafish drug screening experiments.