Treatment Challenges Research Articles

The impact of chronic obstructive pulmonary disease on the risk of immune-related pneumonitis in lung cancer patients undergoing immunotherapy: a systematic review and meta-analysis

BackgroundLung cancer, a leading cause of cancer mortality, poses significant treatment challenges. The use of immune checkpoint inhibitors (ICIs) has revolutionized therapy, but it is associated with immune-related pneumonitis (IRP). This study systematically reviews and analyzes the impact of Chronic Obstructive Pulmonary Disease (COPD) on the risk of IRP in lung cancer patients undergoing immunotherapy.MethodsAdhering to PRISMA guidelines and using the PICO framework, a comprehensive search across PubMed, Embase, Web of Science, and the Cochrane Library was conducted. Inclusion criteria encompassed peer-reviewed studies involving lung cancer patients treated with ICIs, comparing those with and without COPD. The primary outcome was the incidence and risk of IRP. The Newcastle-Ottawa Scale evaluated study quality. The effect size was calculated using random or fixed-effects models based on the observed heterogeneity. We assessed the heterogeneity between studies and conducted a sensitivity analysis.ResultsThe search identified 1026 articles, with six meeting the criteria for inclusion. Studies varied in design and geography, predominantly retrospective cohort studies. Patients with COPD had an increased risk of IRP (OR = 1.54, 95% CI [1.24, 1.92, P < 0.01). Subgroup analysis based on radiation therapy exposure (< 40% and ≥ 40%) also indicated a heightened IRP risk in COPD patients. Sensitivity analysis affirmed the robustness of the results, and publication bias was not significant.ConclusionsLung cancer patients with COPD undergoing immunotherapy have a significantly increased risk of developing IRP. This highlights the necessity for vigilant monitoring and individualized treatment strategies to improve the safety and effectiveness of immunotherapy in this group.

Flow diversion for unruptured MCA bifurcation aneurysms: comparison of p64 classic, p64 MW HPC, and p48 MW HPC flow diverter stents.

MCA bifurcation aneurysms pose treatment challenges because of the complex hemodynamics at the bifurcation and the risk of rupture. FDS implantation has been controversial and there are only limited reports. Therefore, the aim of this study was to assess the efficacy and safety of this treatment strategy using p64 MW HPC and p48 MW HPC FDSs for MCA bifurcation aneurysms, compared with the p64 classic FDS. We retrospectively analyzed our institutional database and identified all patients with saccular, non-ruptured MCA bifurcation aneurysms treated with p64 MW HPC, p48 MW HPC, or p64 classic FDS implantation alone. Aneurysms with implantation of additional devices in the same session, previous treatments, and acutely ruptured and fusiform aneurysms were excluded. A total of 79 aneurysms met the inclusion criteria: 23 receiving a p64 MW HPC, 34 receiving a p48 MW HPC, and 22 receiving a p64 classic FDS. The occlusion rate was highest for the p48 MW HPC 2 mm FDS, at 88.9% at FU2, compared with 72.2% for the p64 MW HPC and 70.6% for the p64 classic. The time to aneurysm occlusion was shortest with the p64 MW HPC, at 178.31 days. The highest retreatment rate was observed with the p48 MW HPC 3 mm. Treatment of MCA bifurcation aneurysms with a p48 MW HPC 2 mm or p64 MW HPC FDS is a safe and reliable strategy achieving high aneurysm occlusion rates - attributable to their lower porosity in relation to the parent vessel diameter as compared to the p48 MW HPC 3 mm FDS-, with reasonable morbidity and mortality.

Nanomaterials in Targeting Cancer Cells with Nanotherapeutics: Transitioning Towards Responsive Systems.

On a global scale, cancer is a difficult and devastating illness. Several problems with current chemotherapies include cytotoxicity, lack of selectivity, stem-like cell growth, and multi-drug resistance. The most appropriate nanomaterials for cancer treatment are those with characteristics, such as cytotoxicity, restricted specificity, and drug capacity and bioavailability; these materials are nanosized (1-100 nm). Nanodrugs are rarely licenced for therapeutic use despite growing research. These compounds need nanocarrier-targeted drug delivery experiments to improve their translation. This review describes new nanomaterials reported in the literature, impediments to their clinical studies, and their beneficial cancer therapeutic use. It also suggests ways to use nanomaterials in cancer therapy more efficiently and describes the intrinsic challenges of cancer treatment and the different nanocarriers and chemicals that can be utilised for specified tumour targeting. Furthermore, it provides a concise overview of cancer theranostics methods, with a focus on those that make use of nanomaterials. Although nanotechnology offers a great source for future advancements in cancer detection and therapy, there is an emerging need for more studies to address the present barriers to clinical translation.

The predictors of coronary slow flow in patients undergoing coronary angiography

BackgroundA new challenge in coronary artery disease treatment has emerged, where specific populations exhibit ischemic symptoms without any obstruction in the epicardial coronary artery. Instead, they exhibit slow coronary contrast flow, referred to as coronary slow flow (CSF). This study aims to identify several predictors of CSF.ResultsThis case–control study was conducted at the Regional General Hospital of West Nusa Tenggara Province in Indonesia from December 2016 to February 2024. The study involved sixty subjects, with 30 in each group of CSF and normal epicardial coronary artery angiogram (NECA). CSF is enforced by the TIMI frame count (TFC) greater than 27 frames. Among all the predictors studied, coronary artery diameter (p < 0.001) and random blood sugar (p = 0.049) were found to affect the CSF significantly. In the multivariate analysis, coronary artery diameter remained a significant predictor (adjusted OR 10.08, 95% CI 2.64–38.50, p < 0.001), with an optimal cut-off point of more than 3.56 mm, a sensitivity of 76.7%, and a specificity of 70.7% (AUC = 0.787, p < 0.001).ConclusionThe coronary artery diameter strongly predicts CSF in patients undergoing coronary angiography.

Phenotypic and molecular characterization of multidrug-resistant Enterobacterales isolated from clinical samples in Palestine: a focus on extended-spectrum β-lactamase- and carbapenemase-producing isolates

BackgroundInfections resulting from multidrug-resistant Enterobacterales (MDR-E) pose a growing global threat, presenting challenges in treatment and contributing significantly to morbidity and mortality rates. The main objective of this study was to characterize phenotypically and genetically extended-spectrum β-lactamase- and carbapenemase- producing Enterobacterales (ESBLE and CPE respectively) isolated from clinical samples in the West Bank, Palestine.MethodsA cross sectional study was conducted in October 2023 on clinical bacterial isolates collected from five governmental hospitals in the West Bank, Palestine. The isolates obtained from the microbiology laboratories of the participating hospitals, underwent identification and antibiotic susceptibility testing (AST) using the VITEK® 2 Compact system. ESBL production was determined by the Vitek2 Compact system. A modified carbapenem inactivation method (mCIM) was employed to identify carbapenemase-producing Enterobacterales (CPE). Resistance genes were detected by real-time PCR.ResultsOut of the total 1380 collected isolates, we randomly selected 600 isolates for analysis. Our analysis indicated that 287 (47.83%) were extended-spectrum beta-lactamase producers (ESBLE), and 102 (17%) as carbapenem-resistant Enterobacterales (CRE) isolates. A total of 424 isolates (70.67%) were identified as multidrug-resistant Enterobacterales (MDRE). The most prevalent ESBL species were K. pneumoniae (n = 124; 43.2%), E. coli (n = 119; 41.5%) and E. cloacae (n = 31; 10.8%). Among the CRE isolates, 85 (83.33%) were carbapenemase-producing Enterobacterales (CPE). The most frequent CRE species were K. pneumoniae (n = 63; 61.7%), E. coli (n = 25; 24.5%) and E. cloacae (n = 13; 12.8%). Additionally, 47 (7.83%) isolates exhibited resistance to colistin (CT), with 38 (37.62%) being CT-resistant CRE and 9 (3.14%) being CT-resistant ESBLE while sensitive to carbapenems. We noticed that 11 isolates (6 Klebsiella pneumoniae and 5 Enterobacter cloacae complex) demonstrated sensitivity to carbapenems by phenotype but carried silent CPE genes (1 blaOXA48, and 6 blaNDM, 4 blaOXA48, blaNDM). ESBL-producing Enterobacterales strains exhibited varied resistance patterns across different antibiotic classes. E. coli isolates showed notable 48% resistance to trimethoprim/sulfamethoxazole. K. pneumoniae isolates displayed a significant resistance to trimethoprim/sulfamethoxazole, nitrofurantoin, and fosfomycin (54%, 90%, and 70% respectively). E. cloacae isolates showed complete resistance to nitrofurantoin and fosfomycin. P. mirabilis isolates exhibited high resistance against fluoroquinolones (83%), and complete resistance to trimethoprim/sulfamethoxazole, nitrofurantoin and fosfomycin.ConclusionThis study showed the high burden of the ESBLE and CRE among the samples collected from the participating hospitals. The most common species were K. pneumoniae and E. coli. There was a high prevalence of blaCTXm. Adopting both conventional and molecular techniques is essential for better surveillance of the emergence and spread of antimicrobial-resistant Enterobacterales infections in Palestine.

Unraveling the Boundaries, Overlaps, and Connections between Schizophrenia and Obsessive-Compulsive Disorder (OCD).

Schizophrenia (SCZ) and obsessive-compulsive disorder (OCD) typically have distinct diagnostic criteria and treatment approaches. SCZ is characterized by delusions, hallucinations, disorganized speech, and cognitive impairments, while OCD involves persistent, intrusive thoughts (obsessions) and repetitive behaviors (compulsions). The co-occurrence of these disorders increases clinical complexity and poses significant challenges for diagnosis and treatment. Epidemiological studies indicate a significant overlap, with prevalence rates of comorbid OCD in SCZ patients ranging from 12% to 25%, which is higher than in the general population. Etiological hypotheses suggest shared genetic, neurobiological, and environmental factors, with genetic studies identifying common loci and pathways, such as glutamatergic and dopaminergic systems. Neuroimaging studies reveal both overlapping and distinct neural abnormalities, indicating shared and unique neurobiological substrates. Environmental factors, like early life stressors and urbanicity, also contribute to the comorbidity. The overlapping clinical features of both disorders complicate diagnosis. Treatment approaches include combining SSRIs with antipsychotics and cognitive behavioral therapy (CBT). The complexity of SCZ and OCD comorbidity underscores the need for a dimensional, spectrum-based perspective on psychiatric disorders, alongside traditional categorical approaches, to improve diagnosis and treatment outcomes.

Treatment Outcomes of Intralesional Steroid Injection for Refractory Vocal Process Granuloma.

Vocal process granuloma (VPG) is a chronic condition resulting from a mucoperichondrial injury of vocal process. Initial conservative treatment typically involves vocal hygiene education and antireflux medication. Treatment challenges arise with refractory cases. Outcomes of second-line treatments such as surgical excision and botulinum toxin injections remain inconsistent. Thus, we propose this study to investigate the effectiveness of intralesional steroid injections for refractory VPG. We conducted a retrospective review of 23 patients with VPG who showed no improvement after 3 months of proton pump inhibitors. These patients underwent one to three courses of monthly in-office intralesional steroid injections as a second-line therapy. Treatment outcomes were evaluated by measuring the size of the VPG relative to the length of the vocal folds before and after the final injection procedure. Results showed a significant reduction in VPG size from baseline of 27.74 ± 15.06 to 5.48 ± 8.95 (p < .001). 15 out of 23 patients were responsive (size reduction ≥ 75%) to intralesional steroid injection. Alcohol consumption and longer symptom duration were associated with a poor response (size reduction <75%), whereas prior intubation was associated with better response. For refractory VPG not responding to conservative treatment, intralesional steroid injection appears to be a promising alternative option without significant adverse effects.

A simple and effective method coupling coagulation and UV/TiO2 photocatalysis for treating real-produced wastewater from oil processing

The complex composition of real-produced wastewater from oil processing poses significant challenges for wastewater treatment. The employed conventional methods have disadvantages such as low efficiency, high-cost demand, secondary waste, adverse effects on the environment and need to be intensified. The combined treatment of coagulation (carried out with Al2(SO4)3) and photocatalysis (UV/TiO2) was studied on wastewater produced from a SOCAR (Pirallahi dry well) oil extraction plant and synthetic paracetamol-based wastewater. Two different dosages of Degussa P25 catalyst at different pH conditions and ion presence were studied. Characterization of the produced wastewater showed the complexity of the treated matrix given the presence of inorganic ions and aromatic and aliphatic contaminants, and an important parameter that was reduced through coagulation was turbidity. The initial concentration expressed as THC was 714 mg/L. At the end of the treatment, a THC value of 210 mg/L was reached.

Comprehensive analysis of flavohemoprotein copy number variation in Giardia intestinalis: exploring links to metronidazole resistance

BackgroundGiardiasis, caused by the protozoan parasite Giardia intestinalis, often presents a treatment challenge, particularly in terms of resistance to metronidazole. Despite extensive research, markers for metronidazole resistance have not yet been identified.MethodsThis study analysed 28 clinical samples of G. intestinalis from sub-assemblage AII, characterised by varying responses to metronidazole treatment. We focussed on copy number variation (CNV) of the multi-copy flavohemoprotein gene, analysed using digital polymerase chain reaction (dPCR) and next generation sequencing (NGS). Additionally, chromosomal ploidy was tested in 18 of these samples. Flavohemoprotein CNV was also assessed in 17 samples from other sub-assemblages.ResultsAnalyses revealed variable CNVs of the flavohemoprotein gene among the isolates, with no correlation to clinical metronidazole resistance. Discrepancies in CNVs detected from NGS data were attributed to biases linked to the whole genome amplification. However, dPCR helped to clarify these discrepancies by providing more consistent CNV data. Significant differences in flavohemoprotein CNVs were observed across different G. intestinalis sub-assemblages. Notably, Giardia exhibits a propensity for aneuploidy, contributing to genomic variability within and between sub-assemblages.ConclusionsThe complexity of the clinical metronidazole resistance in Giardia is influenced by multiple genetic factors, including CNVs and aneuploidy. No significant differences in the CNV of the flavohemoprotein gene between isolates from metronidazole-resistant and metronidazole-sensitive cases of giardiasis were found, underscoring the need for further research to identify reliable genetic markers for resistance. We demonstrate that dPCR and NGS are robust methods for analysing CNVs and provide cross-validating results, highlighting their utility in the genetic analyses of this parasite.Graphical

Extracellular Vesicles in Ovarian Cancer: From Chemoresistance Mediators to Therapeutic Vectors.

Ovarian cancer (OC) remains the deadliest gynecological malignancy, with alarming projections indicating a 42% increase in new cases and a 51% rise in mortality by 2040. This review explores the challenges in OC treatment, focusing on chemoresistance mechanisms and the potential of extracellular vesicles (EVs) as drug delivery agents. Despite advancements in treatment strategies, including cytoreductive surgery, platinum-based chemotherapy, and targeted therapies, the high recurrence rate underscores the need for innovative approaches. Key resistance mechanisms include drug efflux, apoptosis disruption, enhanced DNA repair, cancer stem cells, immune evasion, and the complex tumor microenvironment. Cancer-associated fibroblasts and extracellular vesicles play crucial roles in modulating the tumor microenvironment and facilitating chemoresistance. EVs, naturally occurring nanovesicles, emerge as promising drug carriers due to their low toxicity, high biocompatibility, and inherent targeting capabilities. They have shown potential in delivering chemotherapeutics like doxorubicin, cisplatin, and paclitaxel, as well as natural compounds such as curcumin and berry anthocyanidins, enhancing therapeutic efficacy while reducing systemic toxicity in OC models. However, challenges such as low production yields, heterogeneity, rapid clearance, and inefficient drug loading methods need to be addressed for clinical application. Ongoing research aims to optimize EV production, loading efficiency, and targeting, paving the way for novel and more effective therapeutic strategies in OC treatment. Overcoming these obstacles is crucial to unlocking the full potential of EV-based therapies and improving outcomes for OC patients.

Hybrid construction of tissue-engineered nerve graft using skin derived precursors induced neurons and Schwann cells to enhance peripheral neuroregeneration

Peripheral nerve injury is a major challenge in clinical treatment due to the limited intrinsic capacity for nerve regeneration. Tissue engineering approaches offer promising solutions by providing biomimetic scaffolds and cell sources to promote nerve regeneration. In the present work, we investigated the potential role of skin-derived progenitors (SKPs), which are induced into neurons and Schwann cells (SCs), and their extracellular matrix in tissue-engineered nerve grafts (TENGs) to enhance peripheral neuroregeneration. SKPs were induced to differentiate into neurons and SCs in vitro and incorporated into nerve grafts composed of a biocompatible scaffold including chitosan neural conduit and silk fibroin filaments. In vivo experiments using a rat model of peripheral nerve injury showed that TENGs significantly enhanced nerve regeneration compared to the scaffold control group, catching up with the autograft group. Histological analysis showed improved axonal regrowth, myelination and functional recovery in animals treated with these TENGs. In addition, immunohistochemical staining confirmed the presence of induced neurons and SCs within the regenerated nerve tissue. Our results suggest that SKP-induced neurons and SCs in tissue-engineered nerve grafts have great potential for promoting peripheral nerve regeneration and represent a promising approach for clinical translation in the treatment of peripheral nerve injury. Further optimization and characterization of these engineered constructs is warranted to improve their clinical applicability and efficacy.

Evolution of phenotypic plasticity leads to tumor heterogeneity with implications for therapy.

Cancer is a significant global health issue, with treatment challenges arising from intratumor heterogeneity. This heterogeneity stems mainly from somatic evolution, causing genetic diversity within the tumor, and phenotypic plasticity of tumor cells leading to reversible phenotypic changes. However, the interplay of both factors has not been rigorously investigated. Here, we examine the complex relationship between somatic evolution and phenotypic plasticity, explicitly focusing on the interplay between cell migration and proliferation. This type of phenotypic plasticity is essential in glioblastoma, the most aggressive form of brain tumor. We propose that somatic evolution alters the regulation of phenotypic plasticity in tumor cells, specifically the reaction to changes in the microenvironment. We study this hypothesis using a novel, spatially explicit model that tracks individual cells' phenotypic and genetic states. We assume cells change between migratory and proliferative states controlled by inherited and mutation-driven genotypes and the cells' microenvironment. We observe that cells at the tumor edge evolve to favor migration over proliferation and vice versa in the tumor bulk. Notably, different genetic configurations can result in this pattern of phenotypic heterogeneity. We analytically predict the outcome of the evolutionary process, showing that it depends on the tumor microenvironment. Synthetic tumors display varying levels of genetic and phenotypic heterogeneity, which we show are predictors of tumor recurrence time after treatment. Interestingly, higher phenotypic heterogeneity predicts poor treatment outcomes, unlike genetic heterogeneity. Our research offers a novel explanation for heterogeneous patterns of tumor recurrence in glioblastoma patients.

Engineered nanoparticles potentials in male reproduction.

The escalating prevalence of fertility problems in the aging population necessitates a comprehensive exploration of contributing factors, extending beyond environmental concerns, work-related stress, and unhealthy lifestyles. Among these, the rising incidence of testicular disorders emerges as a pivotal determinant of fertility issues. Current treatment challenges are underscored by the limitations of high-dose and frequent drug administration, coupled with substantial side effects and irreversible trauma inflicted by surgical interventions on testicular tissue. The formidable barrier posed by the blood-testis barrier compounds the complexities of treating testicular diseases, presenting a significant therapeutic obstacle. The advent of nanocarriers, with their distinctive attributes, holds promise in overcoming this impediment. These nanocarriers exhibit exceptional biocompatibility, and membrane penetration capabilities, and can strategically target the blood-testis barrier through surface ligand modification, thereby augmenting drug bioavailability and enhancing therapeutic efficacy. This review concentrates on the transformative potential of nanocarriers in the delivery of therapeutic agents to testicular tissue. By summarizing key applications, we illuminate the strides made in utilizing nanocarriers as a novel avenue to effectively treat testicular diseases. Nanocarriers are critical in delivering therapeutic agents to testicular tissue.

Textural heterogeneity of liver lesions in CT imaging - comparison of colorectal and pancreatic metastases

PurposeTumoral heterogeneity poses a challenge for personalized cancer treatments. Especially in metastasized cancer, it remains a major limitation for successful targeted therapy, often leading to drug resistance due to tumoral escape mechanisms. This work explores a non-invasive radiomics-based approach to capture textural heterogeneity in liver lesions and compare it between colorectal cancer (CRC) and pancreatic cancer (PDAC).Materials and methodsIn this retrospective single-center study 73 subjects (42 CRC, 31 PDAC) with 1291 liver metastases (430 CRC, 861 PDAC) were segmented fully automated on contrast-enhanced CT images by a UNet for medical images. Radiomics features were extracted using the Python package Pyradiomics. The mean coefficient of variation (CV) was calculated patient-wise for each feature to quantify the heterogeneity. An unpaired t-test identified features with significant differences in feature variability between CRC and PDAC metastases.ResultsIn both colorectal and pancreatic liver metastases, interlesional heterogeneity in imaging can be observed using quantitative imaging features. 75 second-order features were extracted to compare the varying textural characteristics. In total, 18 radiomics features showed a significant difference (p < 0.05) in their expression between the two malignancies. Out of these, 16 features showed higher levels of variability within the cohort of pancreatic metastases, which, as illustrated in a radar plot, suggests greater textural heterogeneity for this entity.ConclusionsRadiomics has the potential to identify the interlesional heterogeneity of CT texture among individual liver metastases. In this proof-of-concept study for the quantification and comparison of imaging-related heterogeneity in liver metastases a variation in the extent of heterogeneity levels in CRC and PDAC liver metastases was shown.

BRAIN TUMOR AND EPILEPSY IN CHILDREN: CLINICAL COMPLICATIONS AND SURGICAL TREATMENT

Introduction: Brain tumors in children often present a complex intersection with epilepsy, creating significant challenges for diagnosis and treatment. The presence of brain tumors can lead to the development of epilepsy, which may manifest in various forms depending on the tumor's location and type. Clinical complications include refractory epileptic seizures, neuropsychomotor development impairment, and deterioration in quality of life. Surgical treatment can be crucial for both tumor removal and seizure control, offering the possibility of seizure remission and improving overall prognosis. Objective: The systematic literature review aimed to evaluate the relationship between brain tumors and epilepsy in children, focusing on clinical complications and surgical treatment strategies. Methodology: The methodology followed the PRISMA checklist to ensure a comprehensive and rigorous review. Databases such as PubMed, Scielo, and Web of Science were consulted using descriptors like "pediatric brain tumor," "epilepsy in children," "clinical complications," "surgical treatment," and "pediatric neurosurgery." Inclusion criteria were studies on brain tumors in children, research addressing epilepsy as a symptom or complication, and articles describing surgical treatment. Articles not available in full text, studies outside the pediatric scope, and publications prior to 2014 were excluded. Results: The review revealed that brain tumors can cause epilepsy due to cortical irritation and neural dysfunction. Surgical treatment is often effective in reducing or eliminating epileptic seizures but can be challenging due to the tumor's location and characteristics. Additionally, the results showed that complete tumor resection is associated with better clinical outcomes in terms of seizure control. The literature also highlighted the importance of postoperative monitoring to detect and manage complications. Conclusion: Brain tumors in children frequently lead to epilepsy, and surgical treatment is essential for seizure control and improving quality of life. Complete tumor removal is crucial for positive outcomes, and ongoing monitoring is necessary to manage potential complications. The review highlighted the importance of a multidisciplinary approach to optimize clinical outcomes and patient quality of life.

Severe odontogenic infections in patients with mental disorders—the challenge of ineffective initial treatment

ObjectivesThis study clarified possible delays and deficiencies in severe odontogenic infection (OI) treatment in patients with mental disorders. Study DesignData of hospitalized patients with severe OI were evaluated retrospectively. The outcome variable was preceding health care visits prior to hospitalization. The primary predictor was patient's mental disorder. Explanatory variables were age, sex, smoking, heavy alcohol use, immunocompromised disease or medication, and time span from beginning of symptoms to hospitalization. Also, factors leading to intensive care unit (ICU) care were evaluated. ResultsPreceding visits prior to hospitalization were found in 61 (35.5%) out of 172 patients with OI. In total, 27 patients (15.7%) had a current mental disorder, more commonly in women (26.0%) than in men (8.1%) (P=0.001). Patients with mental disorders had preceding health care visits related to the current infection notably more often than patients without recent psychiatric history (51.9% vs. 32.4%), P=0.053). Patient-related treatment delay remained non-significant. Heavy alcohol use (P=0.010) and smoking (P=0.025) predicted ICU treatment, but no association with patient's mental disorder was found. ConclusionsA patient's mental disorder can complicate diagnosis of OI. Effective and timely treatment requires the professional's ability to simultaneously identify the patient's mental health challenges and progressing OI.

Potential difficult-to-treat psoriatic arthritis real-world prevalence and contributing factors.

The challenge of achieving low disease activity or remission in psoriatic arthritis (PsA) is an unmet need for many patients. Persistent disease activity in PsA may require treatment adjustments due to its complex pathogenesis and varied tissue involvement, highlighting the need for dedicated definitions. This study evaluates patients' frequency and contributing factors with potential "difficult-to-treat PsA (D2TPsA)", similar to the EULAR definition of D2T rheumatoid arthritis. A retrospective study was conducted at two tertiary centres to define potential D2TPsA, defined as failure of ≥1 conventional synthetic disease-modifying anti-rheumatic drug (DMARD) and ≥2 biological or targeted synthetic DMARDs with different mechanisms of action. Of the 171 patients included in the study, 116 (67.8%) were women; the average age was 48.16 ±11.23 years. D2TPsA was detected in 33 patients (19.3%). This group exhibited a longer disease duration, higher disease burden (median number of tender and swollen joints, patient and physician global evaluation, morning stiffness, erythrocyte sedimentation rate and C-reactive protein, DAPSA), HLA-B27 positivity, and higher prevalence of peripheral involvement. Secukinumab usage and mean glucocorticosteroid dosage were significantly higher in the D2TPsA group. Comorbidities such as fibromyalgia (FM) and diabetes mellitus (DM) and the median number of comorbidities were significantly higher in D2TPsA. In multivariate analysis, FM, DM, and HLA-B27 positivity were independently associated with D2TPsA. This study underscores the impact of comorbidities on PsA disease activity and emphasises the need for further research to differentiate treatment challenges influenced by comorbidities from true treatment resistance.

Enhancement of gemcitabine sensitivity in intrahepatic cholangiocarcinoma through Saikosaponin-a mediated modulation of the p-AKT/BCL-6/ABCA1 axis

BackgroundIntrahepatic cholangiocarcinoma (ICC) remains a significant challenge in cancer therapy, especially due to its resistance to established treatments like Gemcitabine, necessitating novel therapeutic approaches. MethodsThis study utilized Gemcitabine-resistant cell lines, patient-derived organotypic tumor spheroids (PDOTs), and patient-derived xenografts (PDX) to evaluate the effects of Saikosaponin-a (SSA) on ICC cellular proliferation, migration, apoptosis, and its potential synergistic interaction with Gemcitabine. Techniques such as transcriptome sequencing, Luciferase reporter assays, and molecular docking were employed to unravel the molecular mechanisms. ResultsSSA exhibited antitumor effects in both in vitro and PDX models, indicating its considerable potential for ICC treatment. SSA markedly inhibited ICC progression by reducing cellular proliferation, enhancing apoptosis, and decreasing migration and invasion. Crucially, it augmented Gemcitabine's efficacy by targeting the p-AKT/BCL6/ABCA1 signaling pathway. This modulation led to the downregulation of p-AKT and suppression of BCL6 transcriptional activity, ultimately reducing ABCA1 expression and enhancing chemosensitivity to Gemcitabine. Additionally, ABCA1 was validated as a predictive biomarker for drug resistance, with a direct correlation between ABCA1 expression levels and the IC50 values of various small molecule drugs in ICC gene profiles. ConclusionThis study highlights the synergistic potential of SSA combined with Gemcitabine in enhancing therapeutic efficacy against ICC and identifies ABCA1 as a key biomarker for drug responsiveness. Furthermore, the introduction of the novel PDOTs microfluidic model provides enhanced insights into ICC research. This combination strategy may provide a novel approach to overcoming treatment challenges in ICC.

Prospective Outcomes After Serial Platelet-Rich Plasma (PRP) Injection in Vocal Fold Scar and Sulcus.

Vocal fold scar and sulcus pose significant treatment challenges with no current optimal treatment. Platelet-rich plasma (PRP), an autologous concentration of growth factors, holds promise for regenerating the superficial lamina propria. This study aims to evaluate the potential benefits of serial PRP injections on mucosal wave restoration and vocal function. In a prospective clinical trial across two institutions, patients with vocal fold scar underwent four serial PRP injections, one month apart. Blinded independent laryngologists and expert listeners used pretreatment and one-month post-fourth injection videostroboscopy and CAPE-V assessments to evaluate mucosal wave and voice quality changes, respectively. Additionally, patient reported outcome measures (PROMs) were evaluated. In the study, 15 patients received 55 PRP injections without adverse effects. Eight patients (53.3%) had mild, three patients (20%) had moderate, and four patients (26.7%) had severe scar. There was an average reduction of 8.7 points in post-treatment VHI-10 scores (p = 0.007). The raters observed an improvement in post-treatment voice in 73.4% of cases, and CAPE-V scores showed a reduction of 18.8 points on average (p = 0.036). The videostroboscopic VALI ratings showed an improvement in mucosal wave rating from 2.0 to 4.0. On average, the raters perceived the post-PRP exams to be better in 56.7% of cases. PRP has been validated as a safe autologous option for treatment of vocal fold scar. While results for mucosal wave and voice quality varied, there was a consistent improvement in PROMs. Level 3: Prospective cohort study, with blinded analysis Laryngoscope, 2024.

Mechanisms of mitophagy and oxidative stress in cerebral ischemia-reperfusion, vascular dementia, and Alzheimer's disease.

Neurological diseases have consistently represented a significant challenge in both clinical treatment and scientific research. As research has progressed, the significance of mitochondria in the pathogenesis and progression of neurological diseases has become increasingly prominent. Mitochondria serve not only as a source of energy, but also as regulators of cellular growth and death. Both oxidative stress and mitophagy are intimately associated with mitochondria, and there is mounting evidence that mitophagy and oxidative stress exert a pivotal regulatory influence on the pathogenesis of neurological diseases. In recent years, there has been a notable rise in the prevalence of cerebral ischemia/reperfusion injury (CI/RI), vascular dementia (VaD), and Alzheimer's disease (AD), which collectively represent a significant public health concern. Reduced levels of mitophagy have been observed in CI/RI, VaD and AD. The improvement of associated pathology has been demonstrated through the increase of mitophagy levels. CI/RI results in cerebral tissue ischemia and hypoxia, which causes oxidative stress, disruption of the blood-brain barrier (BBB) and damage to the cerebral vasculature. The BBB disruption and cerebral vascular injury may induce or exacerbate VaD to some extent. In addition, inadequate cerebral perfusion due to vascular injury or altered function may exacerbate the accumulation of amyloid β (Aβ) thereby contributing to or exacerbating AD pathology. Intravenous tissue plasminogen activator (tPA; alteplase) and endovascular thrombectomy are effective treatments for stroke. However, there is a narrow window of opportunity for the administration of tPA and thrombectomy, which results in a markedly elevated incidence of disability among patients with CI/RI. It is regrettable that there are currently no there are still no specific drugs for VaD and AD. Despite the availability of the U.S. Food and Drug Administration (FDA)-approved clinical first-line drugs for AD, including memantine, donepezil hydrochloride, and galantamine, these agents do not fundamentally block the pathological process of AD. In this paper, we undertake a review of the mechanisms of mitophagy and oxidative stress in neurological disorders, a summary of the clinical trials conducted in recent years, and a proposal for a new strategy for targeted treatment of neurological disorders based on both mitophagy and oxidative stress.