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Cancer Medicine Jun 2023Neoadjuvant chemotherapy followed by radical cystectomy (RC) is the standard of care for patients with muscle-invasive bladder cancer (MIBC). However, treatment outcomes...
BACKGROUND
Neoadjuvant chemotherapy followed by radical cystectomy (RC) is the standard of care for patients with muscle-invasive bladder cancer (MIBC). However, treatment outcomes are suboptimal. Camrelizumab, a PD-1 blockade, has shown benefits in several tumors. This study aimed to investigate the efficacy and safety of neoadjuvant camrelizumab in combination with gemcitabine plus cisplatin (GC) followed by RC for MIBC patients.
METHODS
This was a multi-center, single-arm study that enrolled MIBC patients with a clinical stage of T2-4aN0-1M0, and scheduled for RC. Patients received three 21-day cycles of camrelizumab 200 mg on day 1, gemcitabine 1000 mg/m on day 1 and 8, and cisplatin 70 mg/m on day 2, followed by RC. The primary endpoint was pathologic complete response (pCR, pT0N0).
RESULTS
From May 2020 to July 2021, 43 patients were enrolled and received study medications at nine centers in China. Three of them were deemed ineligible and excluded from efficacy analysis but included in safety analysis. In total 10 patients were unevaluable as they declined RC (two due to adverse events [AEs] and eight due to patient's willingness). Among 30 evaluable patients, 13 patients (43.3%) achieved pCR, and 16 patients (53.3%) achieved pathologic downstaging. No AEs leading to death were observed. The most common AEs were anemia (69.8%), decreased white blood cell count (65.1%), and nausea (65.1%). Immune-related AEs were all grade 1 or 2. Pathologic response was not correlated with PD-L1 expression status or tumor mutation burden. Individual genes as a biomarker for pathologic response were not identified.
CONCLUSIONS
Neoadjuvant treatment with camrelizumab and GC regimen demonstrated preliminary anti-tumor activity for MIBC patients with manageable safety profiles. The study met its primary endpoint, and the following randomized trial is ongoing.
Topics: Humans; Cisplatin; Gemcitabine; Neoadjuvant Therapy; Urinary Bladder Neoplasms; Deoxycytidine; Cystectomy; Muscles; Antineoplastic Combined Chemotherapy Protocols; Neoplasm Invasiveness
PubMed: 37021811
DOI: 10.1002/cam4.5900 -
Translational Lung Cancer Research May 2021A small proportion of patients with non-small cell lung cancer (NSCLC) experience objective clinical benefit after neoadjuvant programmed cell death 1 (PD-1) blockade. A...
BACKGROUND
A small proportion of patients with non-small cell lung cancer (NSCLC) experience objective clinical benefit after neoadjuvant programmed cell death 1 (PD-1) blockade. A neoadjuvant therapeutic regimen combining immune checkpoint blockade with chemotherapy might improve the treatment effect, but such a regimen has not been tested in patients with resectable stage IIIA/IIIB NSCLC.
METHODS
A retrospective study of 35 patients with resectable stage IIIA and IIIB NSCLC who were treated with neoadjuvant chemoimmunotherapy (NCIO) was performed. Patients were evaluated for pathological complete response (pCR), major pathologic response (MPR), safety, and feasibility. The correlations of pathologic response with various clinical factors were studied to identify predictors of pathological response.
RESULTS
NCIO was associated with few immediate adverse events. NCIO did not delay planned surgery and led to a pCR rate of 51.43% and an MPR rate of 74.29% for the primary tumor. No association was observed between programmed death-ligand 1 (PD-L1) expression before NCIO and the pathologic response (Pearson's r=-0.071; P=0.685). However, a significant difference was observed in pathological response in patients with intracavitary and extracavitary tumors (P<0.05). Patients with intracavitary type had a higher pCR (76.47% 31.58%) and MPR (100% 50.00%) rate than patients with extracavitary type (Pearson's r=0.7280; P=0.0009).
CONCLUSIONS
NCIO was associated with few side effects, did not delay surgery, and achieved a pCR in 51.43% and MPR in 74.29% of resected tumors. No significant correlation was found between pathologic response and PD-L1 expression. While the intracavitary and extracavitary tumors type T was predictive of the pathological response to NCIO.
PubMed: 34164269
DOI: 10.21037/tlcr-21-329 -
Pharmaceutics Dec 2023Chronic wounds are a major health challenge that require new treatment strategies. Hydrogels are promising drug delivery systems for chronic wound healing because of... (Review)
Review
Chronic wounds are a major health challenge that require new treatment strategies. Hydrogels are promising drug delivery systems for chronic wound healing because of their biocompatibility, hydration, and flexibility. However, conventional hydrogels cannot adapt to the dynamic and complex wound environment, which involves low pH, high levels of reactive oxygen species, and specific enzyme expression. Therefore, smart responsive hydrogels that can sense and respond to these stimuli are needed. Crucially, smart responsive hydrogels can modulate drug release and eliminate pathological factors by changing their properties or structures in response to internal or external stimuli, such as pH, enzymes, light, and electricity. These stimuli can also be used to trigger antibacterial responses, angiogenesis, and cell proliferation to enhance wound healing. In this review, we introduce the synthesis and principles of smart responsive hydrogels, describe their design and applications for chronic wound healing, and discuss their future development directions. We hope that this review will inspire the development of smart responsive hydrogels for chronic wound healing.
PubMed: 38140076
DOI: 10.3390/pharmaceutics15122735 -
Frontiers in Immunology 2021Rheumatoid arthritis (RA) is a systemic chronic autoinflammatory disease, and the synovial hyperplasia, pannus formation, articular cartilage damage and bone matrix... (Review)
Review
Rheumatoid arthritis (RA) is a systemic chronic autoinflammatory disease, and the synovial hyperplasia, pannus formation, articular cartilage damage and bone matrix destruction caused by immune system abnormalities are the main features of RA. The use of Disease Modifying Anti-Rheumatic Drugs (DMARDs) has achieved great advances in the therapy of RA. Yet there are still patients facing the problem of poor response to drug therapy or drug intolerance. Current therapy methods can only moderate RA progress, but cannot stop or reverse the damage it has caused. Recent studies have reported that there are a variety of long non-coding RNAs (LncRNAs) that have been implicated in mediating many aspects of RA. Understanding the mechanism of LncRNAs in RA is therefore critical for the development of new therapy strategies and prevention strategies. In this review, we systematically elucidate the biological roles and mechanisms of action of LncRNAs and their mechanisms of action in RA. Additionally, we also highlight the potential value of LncRNAs in the clinical diagnosis and therapy of RA.
Topics: Animals; Arthritis, Rheumatoid; B-Lymphocyte Subsets; Biomarkers; Cellular Microenvironment; Combined Modality Therapy; Disease Management; Disease Susceptibility; Gene Expression Regulation; Humans; Immunity; Macrophages; Pathology, Molecular; Prognosis; RNA, Long Noncoding; Signal Transduction; Treatment Outcome
PubMed: 35087527
DOI: 10.3389/fimmu.2021.807738 -
Drug Delivery and Translational Research Aug 2021Inflammation is the biological response of immune system to protect living organisms from injurious factors. However, excessive and uncontrolled inflammation is... (Review)
Review
Inflammation is the biological response of immune system to protect living organisms from injurious factors. However, excessive and uncontrolled inflammation is implicated in a variety of devastating chronic diseases including atherosclerosis, inflammatory bowel disease (IBD), and rheumatoid arthritis (RA). Improved understanding of inflammatory response has unveiled a rich assortment of anti-inflammatory therapeutics for the treatment and management of relevant chronic diseases. Notwithstanding these successes, clinical outcomes are variable among patients and serious adverse effects are often observed. Moreover, there exist some limitations for clinical anti-inflammatory therapeutics such as aqueous insolubility, low bioavailability, off-target effects, and poor accessibility to subcellular compartments. To address these challenges, the rational design of inflammation-specific drug delivery systems (DDSs) holds significant promise. Moreover, as compared to normal tissues, inflamed tissue-associated pathological milieu (e.g., oxidative stress, acidic pH, and overexpressed enzymes) provides vital biochemical stimuli for triggered delivery of anti-inflammatory agents in a spatiotemporally controlled manner. In this review, we summarize recent advances in the development of anti-inflammatory DDSs with built-in pathological inflammation-specific responsiveness for the treatment of chronic inflammatory diseases.
Topics: Anti-Inflammatory Agents; Chronic Disease; Drug Delivery Systems; Humans; Inflammation; Inflammatory Bowel Diseases
PubMed: 33860447
DOI: 10.1007/s13346-021-00977-8 -
Pathogens (Basel, Switzerland) May 2021Genital infection causes severe reproductive pathologies such as salpingitis and pelvic inflammatory disease that can lead to tubal factor infertility. MicroRNAs...
Genital infection causes severe reproductive pathologies such as salpingitis and pelvic inflammatory disease that can lead to tubal factor infertility. MicroRNAs (miRNAs) are evolutionarily conserved regulators of mammalian gene expression in development, immunity and pathophysiologic processes during inflammation and infection, including infection. Among the miRNAs involved in regulating host responses and pathologic outcome of infection, we have shown that miR-378b was significantly differentially expressed during primary infection and reinfection. In this study, we tested the hypothesis that miR-378b is involved in the pathological outcome of infection. We developed miR-378b knockout mice (miR-378b) using Crispr/Cas and infected them along with their wild-type (WT) control with to compare the infectivity and reproductive pathologies. The results showed that miR-378b mice were unable to clear the infection compared to WT mice; also, miR-378b mice exhibited a relatively higher burden throughout the duration of infection. However, gross pathology results showed that miR-378b mice had significantly reduced uterine dilatations and pathologic lesions after two infections compared to WT mice. In addition, the pregnancy and fertility rates for infected miR-378b mice showed protection from -induced infertility with fertility rate that was comparable to uninfected WT mice. These results are intriguing as they suggest that miR-378b is important in regulating host immune responses that control Chlamydial replication and drive the inflammation that causes complications such as infertility. The finding has important implications for biomarkers of Chlamydial complications and targets for prevention of disease.
PubMed: 34067003
DOI: 10.3390/pathogens10050566 -
Acta Biomaterialia Sep 2023A myriad of pH-sensitive scaffolds has been reported in recent decades. Information on their behaviour in vitro under conditions that mimic the pH changes that occur... (Review)
Review
A myriad of pH-sensitive scaffolds has been reported in recent decades. Information on their behaviour in vitro under conditions that mimic the pH changes that occur during tissue regeneration is abundant. Differently, the in vivo demonstration of the advantages of pH-responsive systems in comparison with non-responders is more limited. The in vivo scenario is very complex and the intricate relationship between the host response, the overall pathological conditions of the patient, and the risk of colonization by microorganisms is very difficult to imitate in in vitro tests. This review aims to shed light on how the changes in pH between healthy and damaged states and also during the healing process have been exploited so far to develop polymer-based scaffolds that actively contribute in vivo to the healing process avoiding chronification. The main strategies so far tested to prepare pH-responsive scaffolds rely on (i) changes in ionization of natural polymers, ionizable monomers and clays, (ii) reversible cross-linkers, (iii) coatings, and (iv) production of CO gas. These strategies are analysed in detail in this review with the description of relevant examples of their performance on specific animal models. The versatility of the techniques used to prepare biocompatible and environment-friendly pH-responsive scaffolds that have been implemented in the last decade may pave the way for a successful translation to the clinic. STATEMENT OF SIGNIFICANCE: We report here on the most recent advances in pH-responsive polymer-based scaffolds that have been demonstrated in vivo to be suitable for wound and bone healing. pH is a critical variable in the tissue regeneration process, and small changes can speed up or completely stop the process. Although there is still a paucity of information on the performance in the complex in vivo environment, recently reported achievements using scaffolds endowed with pH-responsiveness through ionic natural polymers, ionizable monomers and clays, reversible cross-linkers, coatings, or formation of CO ensure a promising future towards clinical translation.
Topics: Hydrogen-Ion Concentration; Humans; Animals; Polymers; Cross-Linking Reagents; Tissue Engineering; Clay; Click Chemistry
PubMed: 37482146
DOI: 10.1016/j.actbio.2023.07.025 -
Comprehensive Physiology Jun 2021Successful pregnancy and reproduction are dependent on adequate uterine blood flow, placental perfusion, and vascular responsivity to fetal demands. The ability to...
Successful pregnancy and reproduction are dependent on adequate uterine blood flow, placental perfusion, and vascular responsivity to fetal demands. The ability to support pregnancy centers on systemic adaptation and endometrial preparation through decidualization, embryonic implantation, trophoblast invasion, arterial/arteriolar reactivity, and vascular remodeling. These adaptations occur through responsiveness to endocrine signaling and local uteroplacental mediators. The purpose of this article is to highlight the current knowledge associated with vascular remodeling and responsivity during uterine preparation for and during pregnancy. We focus on maternal cardiovascular systemic and uterine modifications, endometrial decidualization, implantation and invasion, uterine and spiral artery remodeling, local uterine regulatory mechanisms, placentation, and pathological consequences of vascular dysfunction during pregnancy. © 2021 American Physiological Society. Compr Physiol 11:1-23, 2021.
Topics: Female; Humans; Placenta; Placental Circulation; Placentation; Pregnancy; Trophoblasts; Vascular Remodeling
PubMed: 34061977
DOI: 10.1002/cphy.c190015 -
Theranostics 2021Semaphorins are a large family of developmental regulatory signals, characterized by aberrant expression in human cancers. These molecules crucially control cell-cell... (Review)
Review
Semaphorins are a large family of developmental regulatory signals, characterized by aberrant expression in human cancers. These molecules crucially control cell-cell communication, cell migration, invasion and metastasis, tumor angiogenesis, inflammatory and anti-cancer immune responses. Semaphorins comprise secreted and cell surface-exposed molecules and their receptors are mainly found in the Plexin and Neuropilin families, which are further implicated in a signaling network controlling the tumor microenvironment. Accumulating evidence indicates that semaphorins may be considered as novel clinical biomarkers for cancer, especially for the prediction of patient survival and responsiveness to therapy. Moreover, preclinical experimental studies have demonstrated that targeting semaphorin signaling can interfere with tumor growth and/or metastatic dissemination, suggesting their relevance as novel therapeutic targets in cancer; this has also prompted the development of semaphorin-interfering molecules for application in the clinic. Here we will survey, in diverse human cancers, the current knowledge about the relevance of semaphorin family members, and conceptualize potential lines of future research development in this field.
Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Cell Adhesion Molecules; Cell Communication; Cell Movement; Gene Expression Regulation, Neoplastic; Humans; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; Nerve Tissue Proteins; Neuropilins; Prognosis; Semaphorins; Signal Transduction; Survival Analysis; Tumor Microenvironment
PubMed: 33537086
DOI: 10.7150/thno.54023 -
Frontiers in Endocrinology 2024Metabolic syndrome (MetS) and cognitive dysfunction pose significant challenges to global health and the economy. Systemic inflammation, endocrine disruption, and... (Review)
Review
Metabolic syndrome (MetS) and cognitive dysfunction pose significant challenges to global health and the economy. Systemic inflammation, endocrine disruption, and autoregulatory impairment drive neurodegeneration and microcirculatory damage in MetS. Due to their unique anatomy and function, astrocytes sense and integrate multiple metabolic signals, including peripheral endocrine hormones and nutrients. Astrocytes and synapses engage in a complex dialogue of energetic and immunological interactions. Astrocytes act as a bridge between MetS and cognitive dysfunction, undergoing diverse activation in response to metabolic dysfunction. This article summarizes the alterations in astrocyte phenotypic characteristics across multiple pathological factors in MetS. It also discusses the clinical value of astrocytes as a critical pathologic diagnostic marker and potential therapeutic target for MetS-associated cognitive dysfunction.
Topics: Humans; Astrocytes; Metabolic Syndrome; Cognitive Dysfunction; Animals
PubMed: 38800473
DOI: 10.3389/fendo.2024.1393253