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Author(s): Shekhar Neema [1]; Senkadhir Vendhan [2]; Nazir Shah [1]; A. W. Kashif [3]; Biju Vasudevan [4] Epidermolysis bullosa (EB) pruriginosa is a rare and distinctive clinical subset of dystrophic [...]

Background: This study employed a bidirectional Mendelian Randomization (MR) approach to explore the causal relationships between Oral Lichen Planus (OLP), diabetes mellitus (DM), and glycemic control. It also aims to identify potential pharmacological and herbal treatments that effectively address both OLP and the metabolic dysfunctions associated with DM. Methods: This study employs a two-way MR approach to investigate the potential causal relationships between diabetes type and glycated hemoglobin (HbA1c) levels, and the risk of OLP. We analyzed differentially expressed genes from the OLP dataset in the Genomics Expression Omnibus (GEO) database, cross-referencing these with HbA1c-related genes for enrichment analysis. Additionally, the Drug-Gene Interaction Database (DGIdb) and Traditional Chinese Medicine Systems Pharmacology Database (TCMSP) were utilized to assess the effectiveness of specific drugs, herbs, and ingredients in treating OLP while managing blood glucose levels. Results: The MR analysis revealed a significant association between Type 1 Diabetes mellitus (T1DM) and an increased risk of OLP, unlike Type 2 Diabetes mellitus (T2DM). This finding indicates a unique immunological interaction in T1DM that may predispose individuals to OLP. The drug prediction analysis focused on core targets linked to OLP and HbA1c, evaluating the therapeutic potential of retinoic acid, prednisone, and thalidomide for treating OLP and regulating blood glucose levels. Additionally, herbal medicines such as Ecliptae herbaand Amygdalus communis vas, along with herbal ingredients like quercetin, luteolin, and 17-beta-estradiol, were identified for their anti-inflammatory properties and potential to mitigate metabolic dysfunction in diabetes. Conclusion: The study highlighted a complex interplay between diabetes and OLP, underscoring the efficacy of integrated therapeutic strategies that target both conditions. The findings suggest that both pharmaceutical and herbal treatments can effectively manage the clinical manifestations of OLP and associated metabolic challenges. This holistic approach to treatment could significantly enhance patient outcomes by addressing the interconnected aspects of these chronic conditions. [ABSTRACT FROM AUTHOR]

Simple Summary: Our research explores the profile and risk factors for infections in multiple myeloma patients undergoing treatment with daratumumab, a key drug in chemotherapy regimens for this disease. The study seeks to identify which patients are at the highest risk of developing severe infections and the factors contributing to this risk, as infections are a major concern for these patients. Analysis of patient data from our facility showed that lower hemoglobin levels and poorer performance status significantly increase the risk of serious infections. Additionally, we developed predictive algorithms to identify individuals at elevated risk of developing pneumonia during treatment. The findings from our study may help healthcare providers identify high-risk patients and implement targeted strategies to prevent infections, ultimately improving patient care. Background: Daratumumab (Dara) is the first monoclonal antibody introduced into clinical practice to treat multiple myeloma (MM). It currently forms the backbone of therapy regimens in both newly diagnosed (ND) and relapsed/refractory (RR) patients. However, previous reports indicated an increased risk of infectious complications (ICs) during Dara-based treatment. In this study, we aimed to determine the profile of ICs in MM patients treated with Dara-based regimens and establish predictors of their occurrence. Methods: This retrospective, real-life study included MM patients treated with Dara-based regimens between July 2019 and March 2024 at our institution. Infectious events were evaluated using the Terminology Criteria for Adverse Events (CTCAE) version 5.0. Results: The study group consisted of a total of 139 patients, including 49 NDMM and 90 RRMM. In the RR setting, the majority (60.0%) of patients received the Dara, bortezomib, and dexamethasone (DVd) regimen, whereas ND patients were predominantly (98%) treated with the Dara, bortezomib, thalidomide, and dexamethasone (DVTd) regimen. Overall, 55 patients (39.6%) experienced ICs. The most common IC was pneumonia (37.5%), followed by upper respiratory tract infections (26.8%). Finally, twenty-five patients had severe ICs (grade ≥ 3) and required hospitalization, and eight patients died due to ICs. In the final multivariable model adjusted for setting (ND/RR) and age, hemoglobin level (OR 0.77, 95% CI: 0.61–0.96, p = 0.0037), and Eastern Cooperative Oncology Group (ECOG) >1 (OR 4.46, 95% CI: 1.63–12.26, p = 0.0037) were significant factors influencing severe IC occurrence. Additionally, we developed predictive models using the J48 decision tree, gradient boosting, and random forest algorithms. After conducting 10-fold cross-validation, these models demonstrated strong performance in predicting the occurrence of pneumonia during treatment with daratumumab-based regimens. Conclusions: Simple clinical and laboratory assessments, including hemoglobin level and ECOG scale, can be valuable in identifying patients vulnerable to infections during Dara-based regimens, facilitating personalized prophylactic strategies. [ABSTRACT FROM AUTHOR]

COVID-19 pandemic is caused by the SARS-CoV-2 virus, whose internalization and infection are mediated by the angiotensin-converting enzyme 2 (ACE2). The identification of novel approaches to tackle this step is instrumental for the development of therapies for the management of COVID-19 and other diseases with a similar mechanism of infection. Thalidomide, a drug sadly known for its teratogenic effects, has potent immunomodulatory and anti-inflammatory properties. Treatment with this drug has been shown to improve the immune functions of COVID-19 patients and proposed for the management of COVID-19 in clinical practice through drug repositioning. Here, we investigated the molecular details linking thalidomide to ACE2 and COVID-19, showing that in conditions mimicking SARS-CoV-2-associated cytokine storm, the transcription factor ΔNp63α and ACE2 are stabilized, and IL-8 production is increased. In such conditions, we found p63 to bind to and regulate the expression of the ACE2 gene. We previously showed that ΔNp63α is degraded upon thalidomide treatment and now found that treatment with this drug—or with its analogue lenalidomide—downregulates ACE2 in a p63-dependent manner. Finally, we found that thalidomide treatment reduces in vitro infection by pseudo-SARS-CoV-2, a baculovirus pseudotyped with the SARS-CoV-2 spike protein. Overall, we propose the dual effect of thalidomide in reducing SARS-CoV-2 viral re-entry and inflammation through p63 degradation to weaken SARS-CoV-2 entry into host cells and mitigate lung inflammation, making it a valuable option in clinical management of COVID-19. Key messages: Thalidomide treatment results in p63-dependent ACE2 downregulation. ACE2 is a p63 transcriptional target. Thalidomide reduces the "cytokine storm" associated to COVID-19. Thalidomide prevents viral re-entry of SARS-CoV-2 by p63-dependent ACE2 downregulation. Thalidomide is a modulator of SARS-CoV-2 or other ACE2-dependent infections. ACE2 is modulated by a pharmacological substance. [ABSTRACT FROM AUTHOR]

Purpose: As people living with thalidomide embryopathy (TE) are now entering their seventh decade, we examine the impact of ageing and the prevalence of comorbid health conditions reported in holistic needs assessments (HNAs) by individuals with TE, compare it with an age-matched sample of the general population, and explore the relationship between comorbidities and TE pattern of impairment. Materials and methods: The HNA categories were mapped and compared to those of the Health Survey for England (HSE) and analysed across four impairment groups (A–D). Results: 94% (392/415) of individuals with TE residing in the UK participated in the HNA and consented to a secondary analysis of the data. Less than 2% (5/392) reported no comorbidities; 94% reported nervous system problems; including pain, pins and needles and numbness. Individuals with TE reported a significantly greater number of health comorbidities, including musculoskeletal problems, than the age-matched HSE population. Conclusions: Individuals with TE report significantly more health and well-being concerns than the general population of a similar age. Long-term monitoring is needed to ensure that support and rehabilitation services can meet their evolving needs. IMPLICATIONS FOR REHABILITATION: People living with thalidomide's teratogenic effects are now entering their seventh decade. As they age, these individuals experience the long-term consequences linked to over-use of certain joints, including musculoskeletal and neuropathic pain. An understanding of the lived experience of TE with increasing age has the potential to inform the planning and provision of adequate and appropriate rehabilitation services moving forward. Adoption of a holistic approach to rehabilitation could help people living with TE to maintain functional independence as they enter their seventh decade. [ABSTRACT FROM AUTHOR]

The ubiquitin E3 ligase cereblon (CRBN) is the target of therapeutic drugs thalidomide and lenalidomide and is recruited by most targeted protein degraders (PROTACs and molecular glues) in clinical development. Biophysical and structural investigation of CRBN has been limited by current constructs that either require co-expression with the adaptor DDB1 or inadequately represent full-length protein, with high-resolution structures of degrader ternary complexes remaining rare. We present the design of CRBNmidi, a construct that readily expresses from E. coli with high yields as soluble, stable protein without DDB1. We benchmark CRBNmidi for wild-type functionality through a suite of biophysical techniques and solve high-resolution co-crystal structures of its binary and ternary complexes with degraders. We qualify CRBNmidi as an enabling tool to accelerate structure-based discovery of the next generation of CRBN based therapeutics. Structure-based drug discovery of cereblon (CRBN)-recruiting protein degraders has been to date challenging due to limitations with current constructs for recombinant protein expression. In this work, the authors design and validate a truncated CRBN construct, CRBNmidi, that enables crystallization and biophysical characterization of CRBN-binding ligands and degraders. [ABSTRACT FROM AUTHOR]

Thalidomide was used in the 1950s as a sedative. As a result of its marked teratogenicity, it was removed from the market in the 1960s, but returned to the clinic some 40 years later as an antitumor agent. Thalidomide and its derivatives (IMiD and CELMoD) are currently in active use in the treatment of a number of hematological tumors. Its spectrum of properties includes immunomodulatory, anti-inflammatory, and antiangiogenic effects, and neuroprotective and analgesic potentials have been noted. Thalidomide interacts with a component of the ubiquitin ligase complex (cereblon protein), altering its specificity, which leads to proteasomal degradation of a number of neosubstrates, including transcription factors important for embryonic development (SALL4, p63, and PLZF), some which are key for hematological tumors (Ikaros, Aiolos, CK1α, etc.) and some of which regulate the expression of TNF-α mRNA. Discovery of its target contributed to the rapid development of PROTAC technology in the context of seeking a method for intracellular degradation of target proteins. A number of studies addressing the current uses of thalidomide and its analogs are described here. [ABSTRACT FROM AUTHOR]

Radiation-induced oral mucositis (RIOM) is a prevalent oral complication that occurs in individuals undergoing radiotherapy or radiation treatment for head and neck tumors. The presence of oral mucosal rupture and ulcerative lesions, which are the defining features of this condition, can significantly affect the quality of life of patients. Additionally, it can interfere with tumor therapy and contribute to an unfavorable prognosis. Current evidence suggests that cellular inflammation and programmed cell death are important factors in disease development. Moreover, thalidomide (THD) has been revealed to reduce the incidence and severity of RIOM in patients undergoing chemoradiotherapy for nasopharyngeal carcinoma. However, the mechanism through which THD improves RIOM remains unknown. This study aimed to investigate the role of LZTS3 in RIOM by analyzing various sequencing datasets and conducting knockdown and overexpression experiments. We used small interfering RNA transfection and LZTS3 overexpression, followed by validation through polymerase chain reaction, western blotting, flow cytometry, and enzyme-linked immunosorbent assay. In this study, we identified LZTS3 as a potential target for THD regulation in RIOM. Through a series of experiments, we confirmed that LZTS3 has the ability to inhibit the inflammatory response and apoptosis of cells. In addition, we also found that THD can regulate the expression of LZTS3 by upregulating, thereby affecting inflammatory response and apoptosis. We repeated these results in a live animal model. In summary, THD has the potential to reduce the occurrence of oral mucositis in patients by upregulating LZTS3 levels. These findings provide a promising avenue for future drug research and development to treat RIOM. [ABSTRACT FROM AUTHOR]

Background: Recurrent aphthous stomatitis (RAS) is considered as the most common oral mucosal lesion affecting up to 25% of people worldwide. Thalidomide has been reported for the treatment of RAS, but the evidence has not been systematically evaluated. We first systematically reviewed the efficacy and safety of thalidomide for the treatment of RAS. Methods: We searched The Cochrane Library, PubMed, Scopus, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), Chinese BioMedical Literature Database (CBM), Wanfang Data, and VIP information from inception to December 2023. Randomized controlled trials (RCTs) comparing thalidomide with control for RAS were included in the analysis. The primary outcome were complete response and overall response, and the secondary outcome were recurrence interval (RI), ulcer number and size, healing time, visual analogue scale (VAS), immunological data, and adverse events. Meta-analysis was conducted using the Review Manager 5.4 software. Results: Twenty-one trials involving 1668 patients were included in this review. The results of our meta-analysis showed that thalidomide significantly improved the complete response rate and overall response rate, prolonged the recurrence interval, accelerated the healing process, reduced the number and size of ulcers, and lowered TNF-α levels in the treatment of RAS. However, thalidomide significantly increases adverse events. Results: Thalidomide has a significant benefit in the treatment of RAS. However, considering the potential side effects of thalidomide, it may be an optimal treatment option for major RAS patients or cases that do not respond to topical agents. Trial registration: PROSPERO registration number: CRD42024495038. [ABSTRACT FROM AUTHOR]

Background: Hereditary hemorrhagic telangiectasia (HHT) is a disease characterized by arteriovenous malformations and telangiectases, in which the endothelium and immune system play a role in the pathophysiology. Therefore, treatments with antiangiogenic properties which are also regarded as immunomodulators were demonstrated to play an important role in treatment. This systematic review aimed to gather the accumulated information of the use of thalidomide and its analogs in the treatment of HHT. Methods: In this systematic review, publications that were published up to March 2024 and met the inclusion criteria were compiled using the keywords 'thalidomide', 'lenalidomide', 'pomalidomide', 'immunomodulatory drugs' and 'HHT' in Medline and Scholars databases. Results: A total of 53 articles were evaluated and 15 were included in the study. Thalidomide was the predominant used agent and was observed to be used in patients with ages ranging from 37 to 77 years, with doses ranging from 50 to 200 mg daily, and the mean follow-up period was observed to be 6–60 months. Assessments regarding efficacy were based on the epistaxis severity score (ESS), hemoglobin level, and transfusion independence. While thalidomide showed significant efficacy, it also had an adverse event rate of any severity of up to 85% of patients. Use of lenalidomide to control bleeding in HHT was reported in a single case report, while the use of pomalidomide was observed to be investigated in Phase 1 and Phase 2 studies in patients aged 48 to 70 years, with doses ranging from 1 to 5 mg daily for 6–24 months. This treatment was reported to provide significant improvement in hemoglobin levels and ESS. Adverse events of any severity were observed at a frequency of 60–66%. Conclusions: Antiangiogenic agents such as thalidomide, lenalidomide, and pomalidomide may be effective in managing HHT. However, further studies are needed to optimize the timing, dose, and sequence. [ABSTRACT FROM AUTHOR]

The number of therapeutic drugs known to be human teratogens is actually relatively small. This may reflect the rigorous animal testing and well defined labelling. Some of these drugs were identified to have reactive metabolites and this has been postulated, historically, to be their teratogenic mechanism. These drugs include thalidomide, various anticonvulsants and retinoic acid derivatives. Many of these experiments were conducted in a period where chemically reactive metabolites were being intensely investigated and associated with all forms of toxicity. The legacy of this is that these examples are routinely cited as well established mechanisms. Examination of mechanism leads to the conclusion that the teratogenicity in humans of these compounds is likely due to the primary and secondary pharmacology of the parent drug and stable circulating metabolites and that association of reactive metabolites to this toxicity is unwarranted. [ABSTRACT FROM AUTHOR]

Objective: Thalidomide is an effective medication for refractory mucocutaneous lesions of systemic lupus erythematosus (SLE) and can treat arthritis in some autoimmune diseases, but it has some adverse reactions. Recently, the effectiveness of tofacitinib in treating mucocutaneous lesions of SLE has been reported. We aimed to compare the efficacy and safety of tofacitinib with thalidomide in treating mucocutaneous and musculoskeletal lesions in patients with SLE. Methods: This study was a real-world cohort study based on the Chinese SLE Treatment and Research group (CSTAR) registry. SLE patients who manifested mucocutaneous and/or musculoskeletal symptoms and were prescribed tofacitinib or thalidomide were included. We retrospectively conducted comparisons between the tofacitinib and thalidomide groups regarding clinical improvements, SLE disease activity, serological indicators, glucocorticoid doses, and adverse events at the 1, 3, and 6-months time points. Results: At 3 and 6 months, the tofacitinib group exhibited a higher proportion of patients with improvement in mucocutaneous and musculoskeletal issues. Additionally, a greater percentage of patients in the tofacitinib group achieved remission or a low disease activity state (LLDAS) at these time points. No significant serological improvements were observed in either the tofacitinib or thalidomide groups. Fewer adverse events were observed in the tofacitinib group than in the thalidomide group. Conclusions: Tofacitinib might be superior to thalidomide in the improvement of mucocutaneous and musculoskeletal lesions in SLE, and had a good safety profile. [ABSTRACT FROM AUTHOR]

Background Hemoglobin (Hb) Hekinan II (A27; Glu-Asp) is an α-chain variant, and its interaction with the common Southeast Asian (--SEA/) α-thalassemia (α-thal) deletion is rarely reported. This study provides a clinical update of Hb Hekinan II associated with (--SEA/) α-thal. Methods A total of 11 simple heterozygotes and 20 composite heterozygotes for Hb Hekinan II and (--SEA/) α-thal were included based on molecular diagnosis. Results Hb Hekinan II exhibited a significant increase in hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin content, but a decrease in red blood cell level compared with α+ thalassemia deletion. Compared with (--SEA/) α-thal, composite heterozygotes for Hb Hekinan II and (--SEA/) α-thal showed similar erythrocyte parameters. Both heterozygotes with and without (--SEA/) α-thal showed low Hb A2 level. Hb Hekinan II showed abnormal performance in high-performance liquid chromatography but not in capillary electrophoresis. Conclusion Hb Hekinan II is a benign Hb variant. The heterozygotes exhibit clinically asymptomatic coinheritance with (--SEA/) α-thal having comparable hematological phenotype to simple (--SEA/) α-thal. The combination of hematological and molecular analysis helped to improve the detection rate of this rare variant. [ABSTRACT FROM AUTHOR]

Introduction: Lenalidomide, pomalidomide, and thalidomide are effective treatments for multiple myeloma but are teratogenic. To mitigate this risk, the US Food and Drug Administration (FDA) required risk evaluation and mitigation strategy (REMS) programs for these drugs, which include pregnancy testing among women of childbearing potential—twice before initiation, weekly in the first month on treatment, and every 2–4 weeks thereafter. Objective: We evaluated dispensing trends of lenalidomide, pomalidomide, and thalidomide and assessed adherence to REMS pregnancy testing requirements among at-risk patients taking these drugs. Methods: Using three US health insurance claims databases (Optum Clinformatics® [2004–2020], Merative Marketscan [2003–2019], and Medicaid [2000–2018]), we assessed monthly use of the drugs, patient characteristics and treatment persistence among drug initiators, and claims-based evidence for adherence to pregnancy testing requirements among initiators with child-bearing potential. Results: Lenalidomide was the most prescribed agent following its approval in 2006 and through the end of the study period. A total of 48,311 lenalidomide (mean age = 59 years [standard deviation (SD) = 16]), 17,550 thalidomide (mean age = 65 years [SD = 12]), and 6560 pomalidomide initiators (mean age = 65 years [SD = 11]) were identified; 45% of initiators of each drug were women. Among initiators under follow-up on day 90, 70% were still on therapy. Initiators of childbearing potential comprised 3% (N = 1,920) of all initiators; among this cohort, 12% had evidence in claims data of two pregnancy tests before initiation, and 9% with at least 33 days of follow-up of four tests during the first month of treatment. By contrast, 52% who received a refill had claims-based evidence of a pregnancy test within 7 days of dispensing. Conclusion: Although most patients who initiated lenalidomide, pomalidomide, and thalidomide were not of child-bearing potential, further investigation into actual non-adherence to pregnancy testing is needed. [ABSTRACT FROM AUTHOR]

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