Therapeutic Options Research Articles

Advanced nanomedicines and immunotherapeutics to treat respiratory diseases especially COVID-19 induced thrombosis

Immunotherapy and associated immune regulation strategies gained huge attraction in order to be utilized for treatment and prevention of respiratory diseases. Engineering specifically nanomedicines can be used to regulate host immunity in lungs in the case of respiratory diseases including coronavirus disease 2019 (COVID-19) infection. COVID-19 causes pulmonary embolisms, thus new therapeutic options are required to target thrombosis, as conventional treatment options are either not effective due to the complexity of the immune-thrombosis pathophysiology. In this review, we discuss regulation of immune response in respiratory diseases especially COVID-19. We further discuss thrombosis and provide an overview of some antithrombotic nanoparticles, which can be used to develop nanomedicine against thrombo-inflammation induced by COVID-19 and other respiratory infectious diseases. We also elaborate the importance of immunomodulatory nanomedicines that can block pro-inflammatory signalling pathways, and thus can be recommended to treat respiratory infectious diseases.

A comprehensive insight into the immunomodulatory role of MSCs-derived exosomes (MSC-Exos) through modulating pattern-recognition receptors (PRRs).

Mesenchymal stem cell-derived exosomes (MSC-Exos)are emerging as remarkable agents in the field of immunomodulation with vast potential for diagnosing and treating various diseases, including cancer and autoimmune disorders. These tiny vesicles are laden with a diverse cargo encompassing proteins, nucleic acids, lipids, and bioactive molecules, offering a wealth of biomarkers and therapeutic options. MSC-Exos exhibit their immunomodulatory prowess by skillfully regulating pattern-recognition receptors (PRRs).They conduct a symphony of immunological responses, modulating B-cell activities, polarizing macrophages towardanti-inflammatory phenotypes, and fine-tuning T-cell activity. These interactions have profound implications for precision medicine, cancer immunotherapy, autoimmune disease management, biomarker discovery, and regulatory approvals. MSC-Exos promises to usher in a new era of tailored therapies, personalized diagnostics, and more effective treatments for various medical conditions. As research advances, their transformative potential in healthcare becomes increasingly evident.

Mesenchymal Stem Cells-Conditioned Medium; An Effective Cell-Free Therapeutic Option for in vitro Maturation of Oocytes.

Infertility is a major reproductive health issue worldwide. One of the main problems in infertile women is the failure to generate or release a mature egg. Therefore, the development of new technologies for in vitro generation or induction of mature oocytes can improve various ART procedures. Recently, stem cell-based therapy has opened a new window for several pathological complications. Mesenchymal stem cells (MSCs) are multipotent stem cells with the capacity to self-renew and differentiate into the mesodermal lineage. MSCs contain various bioactive molecules which are involved in the regulation of key biological processes. They can secret multiple paracrine factors, such as VEGF, IGF, HGF, EGF, and FGF to stimulate egg maturation. Although MSCs represent a promising source for cell therapy, the potential risk of tumor development reduces their clinical applications. Recent studies have suggested that the supernatant or conditioned medium of MSCs also contains similar components and regulates the oocyte behavior. The MSC-conditioned medium can eliminate the safety concerns associated with MSC transplantation and avoid rejection problems. Although MSC and MSC-CM could improve oocyte quality, ovarian function, and fertility, these improvements have not yet been demonstrated in clinical trials in humans. Hereby, we summarized recent research findings of MSCs-derived conditioned medium in in vitro development of immature oocytes.

Paradigm Shifts in Hodgkin Lymphoma Treatment: From Frontline Therapies to Relapsed Disease.

Combination chemotherapy with or without radiation has served as the primary therapeutic option for classic Hodgkin lymphoma (cHL), leading to durable remission in a majority of patients with early- and advanced-stage cHL. Patients with relapsed/refractory (RR) cHL could still be cured with salvage chemotherapy and autologous stem-cell transplantation. Brentuximab vedotin (BV) and the anti-PD-1-blocking antibodies, nivolumab and pembrolizumab, are highly effective treatments for cHL and have revolutionized the management of the disease. Recent studies incorporating BV and PD-1 blockade into salvage therapy for RR cHL and into frontline treatment regimens have changed the cHL treatment paradigm. The novel agents are also useful in the treatment of older patients who have poor outcomes with traditional therapy. This manuscript will review current strategies for approaching the management of previously untreated, RR, and challenging populations with cHL, including how to incorporate the novel agents.

Preclinical evaluation of combined therapy with amiodarone and low-dose benznidazole in a mouse model of chronic Trypanosoma cruzi infection

Chagasic chronic cardiomyopathy (CCC) is the primary clinical manifestation of Chagas disease (CD), caused by Trypanosoma cruzi. Current therapeutic options for CD are limited to benznidazole (Bz) and nifurtimox. Amiodarone (AMD) has emerged as most effective drug for treating the arrhythmic form of CCC. To address the effects of Bz and AMD we used a preclinical model of CCC. Female C57BL/6 mice were infected with T. cruzi and subjected to oral treatment for 30 consecutive days, either as monotherapy or in combination. AMD in monotherapy decreased the prolonged QTc interval, the incidence of atrioventricular conduction disorders and cardiac hypertrophy. However, AMD monotherapy did not impact parasitemia, parasite load, TNF concentration and production of reactive oxygen species (ROS) in cardiac tissue. Alike Bz therapy, the combination of Bz and AMD (Bz/AMD), improved cardiac electric abnormalities detected T. cruzi-infected mice such as decrease in heart rates, enlargement of PR and QTc intervals and increased incidence of atrioventricular block and sinus arrhythmia. Further, Bz/AMD therapy ameliorated the ventricular function and reduced parasite burden in the cardiac tissue and parasitemia to a degree comparable to Bz monotherapy. Importantly, Bz/AMD treatment efficiently reduced TNF concentration in the cardiac tissue and plasma and had beneficial effects on immunological abnormalities. Moreover, in the cardiac tissue Bz/AMD therapy reduced fibronectin and collagen deposition, mitochondrial damage and production of ROS, and improved sarcomeric and gap junction integrity. Our study underlines the potential of the Bz/AMD therapy, as we have shown that combination increased efficacy in the treatment of CCC.

Application of 20(S)-Protopanaxadiol-Loaded Nanostructured Lipid Carriers for Diabetic Wound Healing and Vascular Regeneration

Chronic wounds in diabetic patients have become a common complication. However, current wound management tends to yield unsatisfactory outcomes and may give rise to complications. Therefore, we prepare a nano-structured lipid carrier by incorporating a 20(S)-Protopanaxadiol (PPD)-loaded lipid nanoparticles (PPD-N) into a silicone elastomer (PPD-NS) for treating chronic diabetic wounds and assess its therapeutic efficacy in promoting diabetic wound healing and vascular regeneration in a mouse model. Our findings revealed that the prepared PPD-N showed uniform distribution with spherical morphology and an average diameter of approximately 130 nm. Moreover, PPD-NS exhibited a wound closure rate of 92.1% after 48 hours of treatment and demonstrated enhanced vascular regeneration. Therefore, it can be concluded that the prepared PPD-NS can effectively be used in diabetic wound repair and vascular regeneration. This study provides a promising potential therapeutic option for diabetic wounds.

Isolation and Characterization of a Novel Mammary Adenocarcinoma, MCa-P1362, with Hormone Receptor Expression, Human Epidermal Growth Factor Receptor 2 Positivity, and Enrichment in Cancer and Mesenchymal Stem Cells

Preclinical models that display spontaneous metastasis are necessary to improve the therapeutic options for hormone receptor-positive breast cancers. Within this study, detailed cellular and molecular characterization was conducted on MCa-P1362, a newly established mouse model of metastatic breast cancer that is syngeneic in BALB/c mice. MCa-P1362 cancer cells express estrogen receptor, progesterone receptor, and the human epidermal growth factor receptor 2. MCa-P1362 cancer cells proliferate invitro and invivo in response to estrogen, yet do not depend on steroid hormones for growth and tumor progression. Analysis of MCa-P1362 tumor explants revealed the tumors contained a mixture of cancer cells and mesenchymal stromal cells. Through transcriptomic and functional analyses of both cancer and stromal cells, stem cells were detected within both populations. Functional studies demonstrated that MCa-P1362 cancer stem cells drove tumor initiation, whereas stromal cells from these tumors contributed to drug resistance. MCa-P1362 may serve as a useful preclinical model to investigate the cellular and molecular basis of breast tumor progression and therapeutic resistance.

Ex vivo sensitivity to broadly neutralizing antibodies and anti-CD4 antibody UB-421 of infectious viral isolates from people living with multidrug-resistant HIV

People living with HIV (PLWH) with multidrug-resistant (MDR) viruses have limited therapeutic options and present challenges regarding clinical management. Recent studies have shown that passive transfer of combination broadly neutralizing antibodies (bNAbs) against HIV and anti-domain 1 CD4 antibody UB-421 can sustain virologic suppression in PLWH in the absence of antiretroviral therapy (ART). Yet studies addressing the therapeutic potential of these antibodies and/or detailed characterization of immunologic and virologic parameters in PLWH with MDR HIV are lacking. We examined levels of immune activation and exhaustion markers on CD8+ T cells and the intact HIV proviral DNA burden in 11 PLWH with MDR viruses. For comparison purposes, we included a control group consisting of 27 ART-naïve viremic PLWH. In addition, we determined the sensitivity of infectious viral isolates obtained from the participants against eight bNAbs (3BNC117, 10-1074, VRC01, VRC07, N6, 10E8, PGDM1400, and PGT121) and two anti-CD4 antibodies (ibalizumab and UB-421) using a TZM-bl-based neutralization/suppression assay. The level of intact HIV proviral DNA was comparable between the two groups (P=0.29). The levels of activation and exhaustion markers PD-1 (P=0.0019), TIGIT (P=0.0222), 2B4 (P=0.0015), CD160 (P=0.0015), and CD38+/HLA-DR+ (P=0.0138) were significantly lower in the MDR group. The infectious viral isolates from each study participant with MDR HIV were resistant to at least 2 bNAbs; however, they were sensitive to at least one of the CD4-binding and non-CD4-binding site antibodies. The majority of participants had ibalizumab-sensitive viruses although the isolates from some participants showed reduced sensitivity to ibalizumab. Notably, none of the 93 viral isolates obtained from the participants were resistant to UB-421. Our data suggest that combination therapy with HIV-specific bNAbs and/or UB-421 in the presence of optimized background therapy could potentially provide sustained virologic suppression in PLWH with MDR HIV. However, this therapeutic strategy needs to be evaluated in human clinical trials. Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

A Comprehensive Review of the Benzimidazole Scaffold as a Potential Nucleus for Anti-Ulcer Activity

Abstract: The benzimidazole scaffold is a promising nucleus for developing novel therapeutic agents for ulcer treatment. Its unique chemical structure provides desirable pharmacological properties, such as excellent bioavailability, metabolic stability, and low toxicity, making it an attractive candidate for ulcer treatment. Several benzimidazole derivatives have shown significant anti-ulcer activity in preclinical and clinical studies, acting through multiple pathways, including inhibition of gastric acid secretion, suppression of gastric inflammation, and promotion of mucosal protection. Some benzimidazole derivatives have also demonstrated anti-Helicobacter pylori activity, suggesting their potential for eradicating bacteria associated with ulcer formation. However, challenges such as poor solubility and limited selectivity remain. Various approaches, such as prodrug design and formulation optimization, have been explored to overcome these issues and improve the therapeutic profile of benzimidazole derivatives. Overall, the benzimidazole scaffold holds great promise as a nucleus for developing novel anti-ulcer agents. Further research and optimization efforts are needed to harness its full potential and translate it into effective treatments for ulcers. With continued advancements in medicinal chemistry and drug design, benzimidazole-based compounds may offer new therapeutic options for patients suffering from ulcers and related gastrointestinal disorders. Hence, this review highlights the knowledge about benzimidazole scaffold, the mechanism of ulcer formation, and various benzimidazole derivatives with anti-ulcer activity, which can be further studied in pre-clinical and clinical trials.

β-lactamase and Plasmid-mediated Quinolone Resistance Determinants Among Proteus spp. Isolates at a Tertiary-care Hospital in Kolkata, India

Background: Emerging antibiotic resistance (ABR) in Proteus spp., especially to third-generation cephalosporins (3GCc), carbapenems, and fluoroquinolones, challenges the treatment outcome and infection prevention. Limited studies pose a knowledge gap between them and ABR. Methods: We investigated the in vitro efficacy of therapeutic options and prevalence of β-lac-tamase and plasmid-mediated quinolone resistance (PMQR) traits in 3GC- and/or fluoroquino-lone-nonsusceptible Proteus (P.) spp. (n=27) in Kolkata, India, during 2021–2022. P. mirabilis was commonly isolated (>80%) from superficial and urine samples. The majority of the isolates (48-78%) remained susceptible to piperacillin-tazobactam, meropenem, amikacin, cefoperazone-sulbactam, and cefepime. Results: All isolates showed >0.2 multiple-antibiotic resistance index, with >65% being multi-drug and >30% being extensively drug-resistant. blaTEM (n=9), blaNDM (n=9), and qnrA (n=6) were commonly noted with the co-production of β-lactamases and PMQR in ten (37%) isolates. More than 50% of the isolates were devoid of the tested acquired genes. Conclusion: The study concludes that superbugs dominate, with limited occurrence of plasmid-borne markers in this geographic location.

Design, 3D-QSAR, molecular docking, ADMET, molecular dynamics and MM-PBSA simulations for new anti-breast cancer agents

Breast cancer is the most frequent form of malignant tumor in women, and represents a major public health problem due to its high mortality rate. Although a multitude of therapeutic options exist for control of this disease, the emergence of resistance to current pharmaceutical treatments underscores the urgency of developing new anti- breast cancer drugs, with a focus on reducing the adverse effects associated with current therapeutic agents. The present study concerns a new series of (23) compounds based on 1,4-quinone and quinoline derivatives to design candidate drugs against breast cancer. For this purpose, integrated computational techniques were applied, including 3D-QSAR, molecular docking and molecular dynamics simulations (MD). CoMFA and CoMSIA were used to build a robust and highly reliable 3D-QSAR models. To validate the model's predictive capabilities, an external validation was carried out. The results of the best model (CoMSIA/SEA) revealed that electrostatic, steric and hydrogen bond acceptor fields had a significant effect on the anti-breast cancer activity of molecules studied. In addition, evaluation of ADMET properties determined whether these newly designed ligands were likely to be selected as drug-candidates. To confirm the binding stability of the selected ligands to aromatase (3S7S) and validate the molecular docking results, molecular dynamics simulations lasting 100 nanoseconds were performed by calculating RMSD, RMSF, RoG, H-bond, SASA and MM-PBSA parameters. As a result, only one designed compound (ligand 5) emerged as the most promising drug candidate for experimental in vitro and in vivo testing, due to its potential inhibition of breast cancer.

Intercontinental Comparison of Immunohistochemical Subtypes Among Individuals With Breast Cancer in South-East Asia and South America: A Scoping Systematic Review and Meta-Analysis of Observational Studies.

Breast cancer (BC) remains a significant global concern, particularly among developing countries in South-East Asia (SEA) and South America (SA). The socioeconomic burdens of oncologic care in those countries were often originated from limited accessibility on attainable therapeutic options and reliability on identifying essential information of cancer cells, i.e., immunohistochemical (IHC) subtyping to determine suitable approaches. The triple-negative breast cancer (TNBC) is among the most aggressive category in breast malignancy, therefore, requiring more specific molecular pathway blocking to exhaust the cells. However, large-scale epidemiological investigation on its rate among BC remains unavailable to date. This study aimed to describe the prevalence of TNBC in the SEA and SA continents since it may guide the future direction of oncologic research and trials. This review focuses on observational studies from the SEA and SA continents from the last decade. Each study represents its country or cities, period of observation, population size, and the TNBC-BC rate as the main outcomes. Therefore, we may also limit the reporting bias originated from same-patient data on the specific occasions. The analysis will be derived to SEA-SA comparison, plus SEA/SA-specific session as processed in Comprehensive Meta-Analysis (CMA) version 3.0. The statistical analysis will be performed in random effects model (REM) within 95% confidence interval (CI). From 46 studies included in the final analysis with a total enlisted population of 34,346 unique individuals with BC, the TNBC rate was higher in the SEA compared to the SA region (19.3% vs. 15.7%; P < 0.05 in 95% CI), with the highest prevalence observed in Vietnam (22.4%) and Peru (17.8%), if it was restricted on countries with two or more studies. Interestingly, both Laos and Argentina possessed significant differences compared to other countries within their respective continents, with the highest and lowest TNBC rates (P < 0.05). The IHC characteristics in SEA differ from those in the SA continent as mainly represented by TNBC prevalence, possibly shaping the course of future trials in the respective region based on IHC expressivity status.

Sodium arsenite induces hepatic stellate cells activation by m6A modification of TGF-β1 during liver fibrosis

The compound known as Sodium arsenite (NaAsO2), which is a prevalent type of inorganic arsenic found in the environment, has been strongly associated with liver fibrosis (LF), a key characteristic of nonalcoholic fatty liver disease (NAFLD), which has been demonstrated in our previous study. Our previous research has shown that exposure to NaAsO2 triggers the activation of hepatic stellate cells (HSCs), a crucial event in the development of LF. However, the molecular mechanism is still unknown. N6-methyladenosine (m6A) modification is the most crucial post-transcriptional modification in liver disease. Nevertheless, the precise function of m6A alteration in triggering HSCs and initiating LF caused by NaAsO2 remains unknown. Here, we found that NaAsO2 induced LF and HSCs activation through TGF-β/Smad signaling, which could be reversed by TGF-β1 knockdown. Furthermore, NaAsO2 treatment enhanced the m6A modification level both in vivo and in vitro. Significantly, NaAsO2 promoted the specific interaction of METTL14 and IGF2BP2 with TGF-β1 and enhanced the TGF-β1 mRNA stability. Notably, NaAsO2-induced TGF-β/Smad pathway and HSC-t6 cells activation might be avoided by limiting METTL14/IGF2BP2-mediated m6A modification. Our findings showed that the NaAsO2-induced activation of HSCs and LF is made possible by the METTL14/IGF2BP2-mediated m6A methylation of TGF-β1, which may open up new therapeutic options for LF brought on by environmental hazards.

Herbal Anti-fungal Cream: A Natural Approach to Onychomycosis Treatment

Abstract: Onychomycosis is a frequent fungal infection of the nails that is difficult to cure and is not well controlled by standard medications, therapeutic options are limited. Herbal remedies have drawn interest as a result of this due to their potential as complementary therapies. The composition and effectiveness of a novel herbal anti-fungal cream that combines the powerful anti-fungal qualities of clove oil, turmeric, and pure peppermint are examined in this abstract. The strong anti-fungal properties of clove oil's high eugenol content are enhanced by curcumin, an anti-inflammatory and anti-microbial compound found in turmeric. Pure peppermint contributes antifungal and calming qualities as well as a pleasant element. The combination of these components offers a viable way to cure onychomycosis, possibly more effectively than conventional therapies because it is allnatural.

Patellar instability in a prothesis knee: MPFL plasty using hamstring tendon

Introduction: instability of the patella remains a frequent cause of failure following arthroplasty; requires treatment and a precise radiological assessment. Several therapeutic options are possible, including ligamentoplasty of the medial patellofemoral ligament, which is increasingly used, thus proving its effectiveness. Observation: we report the case of an octogenarian patient with gonarthrosis of the knee that has been progressing for several years. He benefited from a knee prosthesis, the consequences of which were marked by a progressive lateral tilt of the patella. Technique: installed in the supine position with resumption of the old approach, sampling of the half tendon was carried out with preparation of the graft on the table. The careful release of the joint and preparation of the graft placement sites then the approach to the lateral side of the patella allowed us to expose the external wing on which an external release of the patella was carried out. Fixing the graft was made, with transtendinous passage on the patellar tendon and quadriceps. Fixation on the femoral side was made by two anchors. Immobilization maintained for 45 days. Discussion: The surgical management of patellar instability on total knee prosthesis involves a diversity of surgical techniques which can be used alone or in combination depending on the etiology. Procedures involving soft tissues ranging from simple external release to MPFL plasties, as well as bone procedures which may require changing prosthetic parts in the event of a rotation defect. Conclusion: MPFL plasty is effective in the management of post-arthroplasty patellar instability and has its place in the treatment of patellar dislocations following total knee prosthesis. It is offered either as a complement to other procedures and in particular to a prosthetic revision

Secondary hyperparathyroidism: Update

Secondary hyperparathyroidism is a clinical condition characterized by an increase in the synthesis and secretion of parathyroid hormone (PTH). Its presentation will be conditioned by the development of stimuli such as hyperphosphatemia, hypocalcemia, vitamin D deficiency, and PTH resistance. The most common cause of secondary hyperparathyroidism is chronic kidney disease, a pathological condition in which all the afore mentioned stimuli converge. Secondary hyperparathyroidism is evidenced by an increase in the size of the parathyroid glands, favored by cellular hyperplasia and hypertrophy. At the bone level, there will be an increase in the quantity and activity of osteoblasts and osteoclasts, leading to bone with unusual structural characteristics. Symptoms related to the disease include itching, bone pain, concentration alteration, and depression. In the long term, patients have a higher risk of cardiovascular mortality. Therapeutic options include calcimimetics, phosphate binders, vitamin D supplements, and surgery.

A cross-sectional, multicenter survey of the prevalence and influencing factors for migraine in epilepsy.

Epilepsy and migraine are common chronic neurological disease. Epidemiologic studies and shared pathophysiology and treatment suggest that these two diseases overlap. However, migraine is often underestimated among patients with epilepsy. This study aimed to evaluate the prevalence of migraine and identify the related influencing factors among adult patients with epilepsy. Adult patients with epilepsy were recruited at the outpatient epilepsy clinic of 13 tertiary hospitals in China from February to September 2022. ID Migraine questionnaire was applied to evaluate for migraine. Both univariable and multivariable logistic regression models were used to explore the influencing factors of migraine. A total of 1326 patients with epilepsy were enrolled in this study. The prevalence of migraine among patients with epilepsy was 19.2% (254/1326). In the multivariable analysis, being female (OR = 1.451, 95% CI: 1.068-1.975; p = 0.018), focal and focal to bilateral tonic-clonic seizures (OR = 1.583, 95% CI: 1.090-2.281; p = 0.015), and current seizure attack in the last 3 months (OR = 1.967, 95% CI: 1.282-3.063; p = 0.002) were the influencing factors for migraine. However, <10% of patients with epilepsy received analgesics for migraine. Approximately 20% of patients with epilepsy screened positive for migraine. Being female, focal and focal to bilateral tonic-clonic seizures, and current seizure attack in the last 3 months were the influencing factors for migraine. Neurologists should pay more attention to the screening and management of the migraine among patients with epilepsy in China. Epilepsy and migraine are common chronic neurological disease with shared pathophysiological mechanisms and therapeutic options. However, migraine is often underestimated among patients with epilepsy. This multicenter study aimed to evaluate the prevalence of migraine and current status of treatment. In this study, approximately 20% of patients with epilepsy screened positive for migraine. Female, focal and focal to bilateral tonic-clonic seizures, and current seizure attack in the last 3 months were identified as independent influencing factors for migraine. Despite the high prevalence, the treatment for migraine was not optimistic, neurologists should pay more attention to the screening and management of migraine.

BRAFV600E Metastatic Melanoma Journey: A Perspective from a Patient and his Oncologist.

This article is co-authored by a patient with BRAFV600E metastatic melanoma and his treating oncologist. The patient describes how he coped with his diagnosis and treatment. He details the pathway of his melanoma treatment, which has spanned over 10 years, including surgical interventions, medical treatment, and participation in clinical trials. He relates his experience of living with the disease-and the adverse effects of treatment-in the long term. The clinical perspective of his treating oncologist reviews the diagnostic process and explains how the therapeutic options were selected for and with the patient. The oncologist also addresses the integration of the patient into clinical trials involving programmed death-1 (PD-1) inhibitors and BRAF/MEK inhibitors. Challenges related to the adverse effects that occurred and the personalised treatment of the patient are also discussed. Finally, the article evaluates current advances in treatment and future therapeutic approaches. This case highlights the challenges of identifying which therapeutic options are most appropriate for individual patients with BRAFV600E metastatic melanoma.

Pachyonychia congenita - pathogenesis of pain and approaches to treatment.

Pachyonychia congenita is an autosomal dominant genodermatosis characterized by a triad of chronic severe plantar pain, focal palmoplantar keratoderma, and hypertrophic nail dystrophy. Plantar pain can be debilitating and have a profound impact on quality of life. Current therapeutic options for pain in PC are limited to lifestyle adjustment and mechanical techniques, with a small subgroup of patients benefiting from oral retinoids. This review investigates the pathogenesis of pain in pachyonychia congenita and provides a summary of the current and future therapeutic options.

Hypoxia in Uterine Fibroids: Role in Pathobiology and Therapeutic Opportunities

Uterine fibroids are the most common tumors in females, affecting up to 70% of women worldwide, yet targeted therapeutic options are limited. Oxidative stress has recently surfaced as a key driver of fibroid pathogenesis and provides insights into hypoxia-induced cell transformation, extracellular matrix pathophysiology, hypoxic cell signaling cascades, and uterine biology. Hypoxia drives fibroid tumorigenesis through (1) promoting myometrial stem cell proliferation, (2) causing DNA damage propelling the transformation of stem cells to tumor-initiating cells, and (3) driving excess extracellular matrix (ECM) production. Common fibroid-associated DNA mutations include MED12 mutations, HMGA2 overexpression, and fumarate hydratase loss of function. Evidence suggests an interaction between hypoxia signaling and these mutations. Fibroid development and growth are promoted by hypoxia-triggered cell signaling via various pathways including HIF-1, TGFβ, and Wnt/β-catenin. Fibroid-associated hypoxia persists due to antioxidant imbalance, ECM accumulation, and growth beyond adequate vascular supply. Current clinically available fibroid treatments do not take advantage of hypoxia-targeting therapies. A growing number of pre-clinical and clinical studies identify ROS inhibitors, anti-HIF-1 agents, Wnt/β-catenin inhibition, and TGFβ cascade inhibitors as agents that may reduce fibroid development and growth through targeting hypoxia.