-
Cureus Nov 2023We present an unusual case of a geriatric patient with right-sided cardiac displacement and rotation (Pseudo-Dextrocardia) secondary to radiation-induced pulmonary...
We present an unusual case of a geriatric patient with right-sided cardiac displacement and rotation (Pseudo-Dextrocardia) secondary to radiation-induced pulmonary fibrosis (RIPF) after radiation for carcinoma of the right breast. This patient with heart failure with reduced ejection fraction (HFrEF) underwent cardiac resynchronization therapy with a defibrillator (CRT-D) for primary prevention of sudden cardiac death. Cannulization of the coronary sinus ostium was difficult, likely due to the significant cardiac displacement. However, after multiple attempts, it was eventually successful. The clinical manifestations, evaluation, and technical and procedural issues in this patient with an unusual anatomic variant are summarized.
PubMed: 38073962
DOI: 10.7759/cureus.48454 -
ACS Nano Dec 2023Ongoing research is actively exploring the use of immune checkpoint inhibitors to treat solid tumors by inhibiting the PD-1/PD-L1 axis and reactivating the function of...
Ongoing research is actively exploring the use of immune checkpoint inhibitors to treat solid tumors by inhibiting the PD-1/PD-L1 axis and reactivating the function of cytotoxic T effector cells. Many types of solid tumors, however, are characterized by a dense and stiff stroma and are difficult to treat. Mechanotherapeutics have formed a recent class of drugs that aim to restore biomechanical abnormalities of the tumor microenvironment, related to increased stiffness and hypo-perfusion. Here, we have developed a polymeric formulation containing pirfenidone, which has been successful in restoring the tumor microenvironment in breast tumors and sarcomas. We found that the micellar formulation can induce similar mechanotherapeutic effects to mouse models of 4T1 and E0771 triple negative breast tumors and MCA205 fibrosarcoma tumors but with a dose 100-fold lower than that of the free pirfenidone. Importantly, a combination of pirfenidone-loaded micelles with immune checkpoint inhibition significantly delayed primary tumor growth, leading to a significant improvement in overall survival and in a complete cure for the E0771 tumor model. Furthermore, the combination treatment increased CD4 and CD8 T cell infiltration and suppressed myeloid-derived suppressor cells, creating favorable immunostimulatory conditions, which led to immunological memory. Ultrasound shear wave elastography (SWE) was able to monitor changes in tumor stiffness during treatment, suggesting optimal treatment conditions. Micellar encapsulation is a promising strategy for mechanotherapeutics, and imaging methods, such as SWE, can assist their clinical translation.
Topics: Mice; Animals; Micelles; Immunotherapy; Pyridones; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Tumor Microenvironment
PubMed: 38054429
DOI: 10.1021/acsnano.3c03305 -
Cureus Oct 2023Interstitial lung diseases (ILDs) are a group of disorders affecting the parenchymal tissue of the lungs. This disease leads to complications like pulmonary... (Review)
Review
Interstitial lung diseases (ILDs) are a group of disorders affecting the parenchymal tissue of the lungs. This disease leads to complications like pulmonary hypertension, heart failure, etc. that can affect patients. The etiological factors, clinical features, investigation methods, and diseases are conditions associated with ILD. The history of these conditions is of great value; any history of environmental and occupational exposure, medications, dust, or any toxic inhalation can be a predisposing factor. The CT scan is the investigation of choice in the case of ILD. This article states the recent advances made in treating interstitial lung diseases. The non-pharmacological and pharmacological management of ILD is discussed in the article. The discussion below concerns newer drugs approved by the FDA and their adverse effects, dosages, and contraindications. Below is a detailed conversation about ILD and the recent advances in treating this disease.
PubMed: 38034229
DOI: 10.7759/cureus.48016 -
BMC Pulmonary Medicine Nov 2023Numerous studies have demonstrated the potential of pirfenidone to enhance the prognosis of patients afflicted with idiopathic pulmonary fibrosis (IPF). Although... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Numerous studies have demonstrated the potential of pirfenidone to enhance the prognosis of patients afflicted with idiopathic pulmonary fibrosis (IPF). Although N-acetylcysteine (NAC) is utilized as an antioxidant in IPF treatment, the combination of NAC and pirfenidone has produced inconsistent outcomes in certain studies. To assess the clinical effectiveness and safety of NAC plus pirfenidone (designated as the treatment group) versus pirfenidone monotherapy (designated as the control group), we conducted a systematic review and meta-analysis of randomized controlled trials (RCTs).
METHODS
RCTs of NAC plus pirfenidone were reviewed searching from databases and networks of unpublished and published studies in any language. Using pair-wise meta-analysis, changes in pulmonary function test (PFT) parameters and safety were evaluated.
RESULTS
Two independent reviewers selected and obtained data from 5 RCTs (n = 398), comprising 1 study from Japan, 1 from Europe, and 3 from China. NAS plus pirfenidone as compared to pirfenidone monotherapy for IPF may not reduce the incidence of skin effects(RR 1.26 [95%CI 0.64 to 2.45]) and mortality(RR 0.35 [95%CI 0.07 to 1.68])(both moderate certainty). NAS plus pirfenidone as compared to pirfenidone monotherapy for IPF may not reduce the incidence of at least one side effects(RR 1.00 [95%CI 0.84 to 1.19]; low certainty),severe side effects(RR 0.67 [95%CI 0.30 to 1.47]; low certainty) and gastrointestinal effects(RR 0.67 [95%CI 0.41 to 1.09]; low certainty) with possibly no effect in Δ%DLco(SMD -0.17 [95%CI -0.15 to 0.48]; low certainty). Meanwhile, the effect of NAS plus pirfenidone as compared to pirfenidone monotherapy on ΔFVC(SMD 0.18 [95%CI -0.68 to 1.05]), Δ%FVC(SMD -2.62 [95%CI -5.82 to 0.59]) and Δ6MWT(SMD -0.35 [95%CI -0.98 to 0.28]) is uncertain(extremely low certainty).
CONCLUSION
Moderate certainty evidence suggests that NAS plus pirfenidone, compared to pirfenidone monotherapy for IPF, does not reduce the incidence of skin effects and mortality.
Topics: Humans; Acetylcysteine; Pyridones; Treatment Outcome; Idiopathic Pulmonary Fibrosis
PubMed: 38031002
DOI: 10.1186/s12890-023-02778-w -
Heliyon Nov 2023Idiopathic pulmonary fibrosis (IPF) is an incurable chronic progressive disease with a low survival rate and ineffective therapeutic options. We examined the effects of...
Idiopathic pulmonary fibrosis (IPF) is an incurable chronic progressive disease with a low survival rate and ineffective therapeutic options. We examined the effects of imrecoxib, a nonsteroidal anti-inflammatory drug, on experimental pulmonary fibrosis. The mouse IPF model was established by intratracheal instillation of bleomycin. From Day 0 to Day 13, the mice were orally administered imrecoxib (100 mg/kg) and pirfenidone (200 mg/kg) daily, and from Day 7 to Day 13, the mice were orally administered pirfenidone and imrecoxib daily. The tissues were dissected on the 14th day. Mouse body weight was measured, and histopathological examination and hydroxyproline content analysis confirmed that the administration of imrecoxib exerted a similar effect to pirfenidone. Compared with bleomycin-induced mice, imrecoxib-treated mice showed significantly reduced inflammatory factor expression (IL-1 and TNF-α) and inflammatory cell numbers (macrophages, lymphocytes, and neutrophils) in BALF (bronchoalveolar lavage fluid). Our experiment tested the ability of imrecoxib to inhibit the signal pathway involved in gene expression induced by TGF-β1 in the NIH-3T3 cell line in vitro. Western blotting showed that imrecoxib (20 μM and 40 μM) inhibited the expression of fibronectin, type I collagen and CTGF. In addition, imrecoxib reduced the levels of -ERK1/2. The changes in the expression of related proteins in mouse lung tissue were similar to those in cells. In summary, our findings suggested that the administration of imrecoxib prevented and treated murine IPF by inhibiting inflammation and the TGF-β1-ERK1/2 signaling pathway.
PubMed: 38027732
DOI: 10.1016/j.heliyon.2023.e20914 -
Immunity, Inflammation and Disease Nov 2023Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating lung disease characterized by irreversible scarring of the lungs. The cause of IPF is unknown, but... (Review)
Review
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating lung disease characterized by irreversible scarring of the lungs. The cause of IPF is unknown, but it is thought to involve a combination of genetic and environmental factors. There is no cure for IPF, and treatment is focused on slowing disease progression and relieving symptoms.
AIMS
We aimed in this review to investigate and provide the latest insights into IPF management modalities, including the potential of Saracatinibas a substitute for current IPF drugs. We also investigated the therapeutic potential of Sotatercept in addressing pulmonary hypertension associated with IPF.
MATERIALS AND METHODS
We conducted a comprehensive literature review of relevant studies on IPF management. We searched electronic databases, including PubMed, Scopus, Embase, and Web of science.
RESULTS
The two Food and Drug Administration-approved drugs for IPF, Pirfenidone, and Nintedanib, have been pivotal in slowing disease progression, yet experimental evidence suggests that Saracatinib surpasses their efficacy. Preclinical trials investigating the potential of Saracatinib, a tyrosine kinase inhibitor, have shown to be more effective than current IPF drugs in slowing disease progression in preclinical studies. Also, Sotatercept,a fusion protein, has been shown to reduce pulmonary vascular resistance and improve exercise tolerance in patients with PH associated with IPF in clinical trials.
CONCLUSIONS
The advancements discussed in this review hold the promise of improving the quality of life for IPF patients and enhancing our understanding of this condition. There remains a need for further research to confirm the efficacy and safety of new IPF treatments and to develop more effective strategies for managing exacerbations.
Topics: United States; Humans; Hypertension, Pulmonary; Quality of Life; Idiopathic Pulmonary Fibrosis; Disease Progression
PubMed: 38018591
DOI: 10.1002/iid3.1079 -
BioRxiv : the Preprint Server For... Nov 2023Increased deposition of extracellular matrix (ECM) components such as collagens and hyaluronan contributes to the pathogenesis of obesity-associated insulin resistance...
Increased deposition of extracellular matrix (ECM) components such as collagens and hyaluronan contributes to the pathogenesis of obesity-associated insulin resistance in muscle, liver, and adipose tissue. Despite the significance of the heart in cardiovascular and metabolic diseases, maladaptive ECM remodelling in obesity-associated cardiac insulin resistance and cardiac dysfunction has not been studied. Using genetic and pharmacological approaches in mice fed a high fat (HF) diet, we demonstrated a tight association between increased ECM deposition with cardiac insulin resistance. Increased collagen deposition by genetic deletion of matrix metalloproteinase 9 (MMP9) exacerbated cardiac insulin resistance and decreased hyaluronan deposition by treatment with PEGylated human recombinant hyaluronidase PH20 (PEGPH20) improved cardiac insulin resistance in obese mice. These relationships corresponded to functional changes in the heart. PEGPH20 treatment in obese mice ameliorated HF diet-induced abnormal myocardial remodelling. In addition to hyaluronan, increased collagen deposition is a characteristic of the obese mouse heart. We further demonstrated that pirfenidone, a clinically available anti-fibrotic medication which inhibits collagen expression, improved cardiac insulin resistance and cardiac function in obese mice. Our results provide important new insights into the role of ECM remodelling in the pathogenesis of cardiac insulin resistance and associated dysfunction in obesity of distinct mouse models. These findings support the novel therapeutic potential of targeting early cardiac ECM abnormalities in the prevention and treatment of obesity-related cardiovascular complications.
PubMed: 38014154
DOI: 10.1101/2023.11.14.567128 -
Life (Basel, Switzerland) Oct 2023Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with a poor prognosis. Pirfenidone is approved and widely used for the treatment of IPF and...
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with a poor prognosis. Pirfenidone is approved and widely used for the treatment of IPF and reduces lung function decline. The aim of this study was to evaluate the efficacy of different doses of pirfenidone for the prevention of disease progression in patients with IPF.
METHODS
This was a prospective, observational, single-center cohort study conducted in Haeundae Paik Hospital, Republic of Korea, from April 2021 to March 2023. IPF patients were assigned to three groups according to the dose of pirfenidone (600 mg, 1200 mg, 1800 mg). Disease progression was defined as an absolute decline to ≥5% of forced vital capacity (FVC) (% predicted value) or an absolute decline to ≥10% of diffusing capacity of the lung for carbon monoxide (DLco) (% predicted value) over 12 months. The primary endpoint was to evaluate the clinical effects of pirfenidone of each dosage on disease progression in IPF patients by comparing the FVC (% predicted value) and DLco (% predicted value) values over 12 months. The secondary endpoint was to evaluate the prognostic value of Krebs von den Lungen-6 (KL-6) in the disease progression in IPF patients using the baseline KL-6 value and the change in KL-6 values between the baseline and 12 months.
RESULTS
A total of 44 patients were enrolled, of whom 39 completed the study, with 13 patients assigned to each of the three groups. The median age was 71.7 years, and 79.5% of patients were men. The baseline characteristics were similar across groups, except the 600 mg group was older (75.9 vs. 69.2 vs. 68.2 years, = 0.016). The overall median change in FVC and DLco over 12 months was -2.7% (IQR: -9.1%, -1.2%) and -3.8% (IQR: -13.6%, -3.7%), respectively. There was no difference in the decline in FVC (change in FVC, % predicted value: -3.23 vs. -4.08 vs. -1.54, = 0.621) and DLco (change in DLco, % predicted value: 0.00 vs. -3.62 vs. -3.15, = 0.437) among the three groups. Fourteen patients (35.9%) suffered disease progression. The rate of disease progression did not differ according to the dose of pirfenidone (38.5 vs. 38.5 vs. 30.8%, = 1.000). In multivariable logistic regression analysis, KL-6 was not a statistically significant predictor of disease progression.
CONCLUSIONS
In our study, regardless of dose, consistent pirfenidone use for 12 months resulted in similar efficacy for the prevention of disease progression in patients with IPF. Large-scale, randomized, double-blind, placebo-controlled clinical trials are needed.
PubMed: 38004258
DOI: 10.3390/life13112118 -
Translational Vision Science &... Nov 2023Trabecular meshwork (TM) fibrosis is a crucial pathophysiological process in the development of primary open-angle glaucoma. Pirfenidone (PFD) is a new, broad-spectrum...
PURPOSE
Trabecular meshwork (TM) fibrosis is a crucial pathophysiological process in the development of primary open-angle glaucoma. Pirfenidone (PFD) is a new, broad-spectrum antifibrotic agent approved for the treatment of idiopathic pulmonary fibrosis. This study investigated the inhibitory effect of PFD on TM fibrosis and evaluated its efficacy in lowering intraocular pressure (IOP).
METHODS
Human TM cells were isolated, cultured, and characterized. Cell Counting Kit-8 was used to evaluate the proliferation and toxicity of different concentrations of PFD on normal or fibrotic TM cells. TM cells were treated with transforming growth factor beta-2 (TGF-β2) in the absence or presence of PFD. Western blotting and immunofluorescence analyses were used to analyze changes in the TM cell cytoskeleton and extracellular matrix (ECM) proteins, including alpha-smooth muscle actin (α-SMA), F-actin, collagen IV (COL IV), and fibronectin (FN). An ocular hypertension (OHT) mouse model was induced with Ad-TGF-β2C226/228S and then treated with PFD or latanoprost (LT) eye drops to confirm the efficacy of PFD in lowering IOP.
RESULTS
PFD inhibited the proliferation of fibrotic TM cells in a dose-dependent manner and inhibited TGF-β2-induced overexpression of α-SMA, COL IV, and FN in TM cells. PFD stabilized F-actin. In vivo, PFD eye drops reduced the IOP of the OHT models and showed no significant difference compared with LT eye drops.
CONCLUSIONS
PFD inhibited TGF-β2-induced TM cell fibrosis by rearranging the disordered cytoskeleton and decreasing ECM deposition, thereby enhancing the aqueous outflow from the TM outflow pathway and lowering IOP, which provides a potential new approach to treating glaucoma.
TRANSLATIONAL RELEVANCE
Our work with pirfenidone provides a new approach to treat glaucoma.
Topics: Animals; Humans; Mice; Actins; Cells, Cultured; Fibrosis; Glaucoma; Glaucoma, Open-Angle; Ocular Hypertension; Ophthalmic Solutions; Trabecular Meshwork; Transforming Growth Factor beta2
PubMed: 37975842
DOI: 10.1167/tvst.12.11.21 -
Advanced Science (Weinheim,... Jan 2024BRD4 is a member of the BET protein family involved in chromatin remodeling and transcriptional regulation. Several BET inhibitors (BETi) have entered clinical trials,...
BRD4 is a member of the BET protein family involved in chromatin remodeling and transcriptional regulation. Several BET inhibitors (BETi) have entered clinical trials, demonstrating potential in inducing cancer cell apoptosis and tumor regression. However, resistance to BETi is common in solid tumors. In pancreatic cancer, it is found that cancer-associated fibroblasts (CAFs) in the tumor microenvironment reduce the BET inhibitor JQ1 sensitivity by inducing BRD4 expression. Moreover, CAFs play a crucial role in the formation of a dense stromal barrier. Therefore, targeting CAFs in the tumor microenvironment of pancreatic cancer not only enhances cancer cells sensitivity to JQ1 but also increases drug perfusion and improves oxygen supply, thus reducing glycolysis and limiting energy supply. To address this challenge, a homologous targeting mechanism utilizing activated fibroblast membrane-coated liposomes is proposed for specific drug precise target to CAFs-rich pancreatic cancer. Additionally, TAT peptides enable liposomes penetration, delivering PFD for targeted anti-fibrotic therapy, reducing extracellular matrix generation and glycolysis, and enhancing JQ1 delivery and sensitivity. In conclusion, the findings indicate the tremendous potential of this CAFs-targeting liposomal delivery system in pancreatic cancer.
Topics: Humans; Liposomes; Cancer-Associated Fibroblasts; Nuclear Proteins; Biomimetics; Cell Line, Tumor; Transcription Factors; Pancreatic Neoplasms; Carcinoma, Pancreatic Ductal; Antineoplastic Agents; Tumor Microenvironment; Bromodomain Containing Proteins; Cell Cycle Proteins
PubMed: 37968249
DOI: 10.1002/advs.202305279