Combination Treatment Strategies Research Articles

Antioxidant anthocyanin synergistic immune enhancer nanopeptide C-I20 remarkably enhances the protective effect of largemouth bass against largemouth bass ranavirus

Largemouth bass ranavirus (LMBV) infection results in huge economic losses in largemouth bass (Micropterus salmoides) industry. Nanopeptide C-I20 and anthocyanins have a positive effect on promoting immune responses and antioxidant mechanisms in several aquatic organisms, and are therefore used to inhibit LMBV infection. In this study, we developed an LMBV immersion challenge model using three different viral concentrations (1×104 copies/mL, 1×105 copies/mL, and 1×106 copies/mL) to infect largemouth bass, and LMBV-MCP mRNA expression was detected in infected fish. Following infection, the fish exhibited severe external ulceration, redness swelling, and darkening of the skin. Histopathological examination revealed significant necrosis and inflammation in muscle tissue, epithelial cell shedding in renal tubules, macrophage aggregation centers and cellular vacuolization in spleen and head kidney, and cellular hypertrophy in liver. To mitigate LMBV infection, we explored the protective effects of a combined treatment strategy involving C-I20 and anthocyanin. Overall, the combination of anthocyanin and C-I20 demonstrated the highest protective efficacy, significantly reducing viral loads in muscle, liver, spleen, and head kidney. Moreover, this treatment regimen enhanced antioxidant enzyme activities (T-AOC, TSOD, GSH-Px, CAT) and modulated important immune genes (IL-1, IL-8, TNF-α, IL-10, Mx, and IgM) expression. In conclusion, the synergistic application of anthocyanin and C-I20 demonstrates significant efficacy in mitigating LMBV infection. This research introduces a novel and promising approach to managing infectious diseases in aquaculture settings.

Bibliometric Analysis to Improve Combined Treatment Strategies for Glioblastoma in America

Introduction: Bibliometric analysis quantitatively examines scientific literature to extract insights. This article has conducted such analysis on glioblastoma multiforme (GBM) treatment articles. GBM, a prevalent brain tumor, is typically treated with surgery, radiation, and chemotherapy. Objectives: The article aimed to bibliometrically analyze articles discussing combined GBM treatment to identify impactful research areas and encourage collaboration. Materials and Methods: The study encompassed a comprehensive search in the Scopus database, spanning articles published from 1974 to 2022. Inclusion criteria encompassed research conducted in the Americas, both clinical and experimental. A total of 772 articles were collected and categorized based on their primary focus on combined treatment approaches. Results: Clinical studies constituted 52% of articles, suggesting a slight dominance. The analysis unveiled key research moments, including a 1998 focus shift and a pivotal 2005 study on temozolomide- radiation combination. Top journals, trends, and authors were identified, with the USA leading in contributions. Discussions: Despite high brain tumor incidence, research distribution discrepancy is concerning. Regional epidemiological studies have been endorsed. The dominance of US and German authors in GBM collaboration has raised equity issues due to budget and GDP disparities limiting Latin American representation. Conclusion: GBM research in the region is dominated by the USA, while contributions from Latin American countries remain limited. The absence of comprehensive epidemiological studies on GBM in Latin America is concerning, considering the evident impact of the disease in the region. This underscores the urgent need for increased research participation and collaboration to advance the understanding and treatment of GBM across Latin American nations.

Antiviral combination treatment strategies for SARS-CoV-2 infection in immunocompromised patients.

The purpose of this review is to report the available evidence regarding the use of combination regimens of antivirals and/or antibody-based therapy in the treatment of SARS-CoV-2 in immunocompromised patients. Literature search identified 24 articles, excluding single case reports, which included mainly patients with hematological malignancies and/or B-cell depletion. Data were divided based on the timing and reason for administration of combination treatment, that is, early treatment to prevent progression to severe COVID-19 and treatment of prolonged or relapsed infection. We described the treated populations, treatment duration and composition of combination treatment. We briefly addressed new treatment options and we proposed an algorithm for the management of COVID-19 infection in patients affected by hematological malignancies. Combination treatment seems an effective (73-100%) and well tolerated (<5% reported bradycardia, hepatotoxicity, neutropenia) strategy for treating prolonged/relapsed SARS-CoV-2 infections in the immunocompromised host, although its optimal composition and duration cannot be defined based on the currently available evidence. The role of combination treatment as an early treatment strategy for immunocompromised patients at a high risk of progression to severe disease/persistent shedding requires further evidence from comparison with monotherapy, even though high efficacy was reported for combinations of antivirals plus mAbs in case of previous viral variants.

Novel combination therapy using recombinant oncolytic adenovirus silk hydrogel and PD-L1 inhibitor for bladder cancer treatment

Recombinant oncolytic adenovirus offers a novel and promising cancer treatment approach, but its standalone efficacy remains limited. This study investigates a combination treatment strategy by co-administering recombinant oncolytic Adv-loaded silk hydrogel with a PD-L1 inhibitor for patients with bladder cancer to enhance treatment outcomes. Bladder cancer tissues from mice were collected and subjected to single-cell sequencing, identifying CRB3 as a key gene in malignant cells. Differential expression and functional enrichment analyses were performed, validating CRB3’s inhibitory role through in vitro experiments showing suppression of bladder cancer cell proliferation, migration, and invasion. Recombinant oncolytic adenoviruses encoding CRB3 and GM-CSF were constructed and encapsulated in silk hydrogel to enhance drug loading and release efficiency. In vivo experiments demonstrated that the nano-composite hydrogel significantly inhibited tumor growth and increased immune infiltration in tumor tissues. Co-administration of adenovirus silk hydrogel (Adv-CRB3@gel) with a PD-L1 inhibitor significantly enhanced T-cell infiltration and tumor killing. The combination of recombinant oncolytic Adv-loaded nano-composite hydrogel encoding CRB3 and GM-CSF with a PD-L1 inhibitor improves bladder cancer treatment outcomes by effectively recruiting T cells, providing a novel therapeutic strategy.

Synergistic combination of perphenazine and temozolomide suppresses patient-derived glioblastoma tumorspheres.

Glioblastoma (GBM), a primary malignant brain tumor, has a poor prognosis, even with standard treatments such as radiotherapy and chemotherapy. In this study, we explored the anticancer effects of the synergistic combination of perphenazine (PER), a dopamine receptor D2/3 (DRD2/3) antagonist, and temozolomide (TMZ), a standard treatment for GBM, in patient-derived human GBM tumorspheres (TSs). The biological effects of the combination of PER and TMZ in GBM TSs were assessed by measuring cell viability, ATP, stemness, invasiveness, and apoptosis. Changes in protein and mRNA expression were analyzed using western blotting and RNA sequencing. Co-administration of PER and TMZ was evaluated in vivo using a mouse orthotopic xenograft model. The Severance dataset showed that DRD2 and DRD3 expression was higher in tumor tissues than in the tumor-free cortex of patients with GBM. DRD2/3 knockout by CRISPR/Cas9 in patient-derived human GBM TSs inhibited cell growth and ATP production. The combined treatment with PER and TMZ resulted in superior effects on cell viability and ATP assays compared to those in single treatment groups. Flow cytometry, western blotting, and RNA sequencing confirmed elevated apoptosis in GBM TSs following combination treatment. Additionally, the combination of PER and TMZ downregulated the expression of protein and mRNA associated with stemness and invasiveness. In vivo evaluation showed that combining PER and TMZ extended the survival period of the mouse orthotopic xenograft model. The synergistic combination of PER and TMZ has potential as a novel combination treatment strategy for GBM.

La radiothérapie des CBNPC de stade III : nouvelles techniques, nouvelles combinaisons

Defining the optimal treatment approach for patients with stage III non-small cell lung cancer, where the loco-regional disease extension renders a surgical approach obsolete, represents an important clinical challenge. In addition, many of these patients present with several comorbidities, compromising their tolerance to treatment. This article describes how innovative radiotherapy approaches try to enhance loco-regional tumour control as a first step towards improved survival, often by exploring novel avenues to dose-escalation, while at the same time focus on limiting early and long-term radiation-induced toxicity by applying the most advanced radiotherapy techniques. Moreover, the path towards new combinations with systemic agents, particularly immunotherapy building on the actual standard of combined chemo-radiotherapy with durvalumab in consolidation, is reported. This article wants to give a balanced view on the importance to investigate how we can obtain better local and metastatic disease control by intensifying our combined treatment strategies, while bearing in mind that many of our patients in daily clinical practice may not be able tolerate this. This urges us to also explore less disruptive treatment approaches for our more frail and aged patient population and define in a multidisciplinary manner the most optimal treatment strategy for each individual patient in our daily clinical practice.1877-1203/© 2024 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Integrative Modeling of Signaling Network Dynamics Identifies Cell Type-Selective Therapeutic Strategies for FGFR4-Driven Cancers.

Oncogenic FGFR4 signaling represents a potential therapeutic target in various cancer types, including triple-negative breast cancer and hepatocellular carcinoma. However, resistance to FGFR4 single-agent therapy remains a major challenge, emphasizing the need for effective combinatorial treatments. Our study sought to develop a comprehensive computational model of FGFR4 signaling and to provide network-level insights into resistance mechanisms driven by signaling dynamics. An integrated approach, combining computational network modeling with experimental validation, uncovered potent AKT reactivation following FGFR4 targeting in triple-negative breast cancer cells. Analyzing the effects of cotargeting specific network nodes by systematically simulating the model predicted synergy of cotargeting FGFR4 and AKT or specific ErbB kinases, which was subsequently confirmed through experimental validation; however, cotargeting FGFR4 and PI3K was not synergistic. Protein expression data from hundreds of cancer cell lines was incorporated to adapt the model to diverse cellular contexts. This revealed that although AKT rebound was common, it was not a general phenomenon. For example, ERK reactivation occurred in certain cell types, including an FGFR4-driven hepatocellular carcinoma cell line, in which there is a synergistic effect of cotargeting FGFR4 and MEK but not AKT. In summary, this study offers key insights into drug-induced network remodeling and the role of protein expression heterogeneity in targeted therapy responses. These findings underscore the utility of computational network modeling for designing cell type-selective combination therapies and enhancing precision cancer treatment. Significance: Computational predictive modeling of signaling networks can decipher mechanisms of cancer cell resistance to targeted therapies and enable identification of more effective cancer type-specific combination treatment strategies.

Emodin combined with 5-aminolevulinic acid photodynamic therapy inhibits condyloma acuminate angiogenesis by targeting SerRS.

Human papillomavirus (HPV) infection can cause condyloma acuminatum (CA), which is characterized by a high incidence and a propensity for recurrence after treatment. Angiogenesis plays an important role in the occurrence and development of CA. Seryl-tRNA synthetase (SerRS) is a newly identified, potent anti-angiogenic factor that directly binds to the vascular endothelial growth factor (VEGFA) promoter, thereby suppressing its transcription. Emodin is a natural anthraquinone derivative that can promote SerRS expression. This study aimed to investigate the effects of emodin on CA and explore combined treatment strategies. The HPV-infected cell line SiHa was treated with either DMSO, emodin, ALA-PDT or a combination of emodin and ALA-PDT. We observed the effects on cell proliferation, apoptosis and the SerRS-VEGFA pathway. Our findings demonstrated that emodin targets angiogenesis through the SerRS-VEGFA pathway, resulting in the inhibition of SiHa cell proliferation and promotion of apoptosis (p < 0.001). To verify the therapeutic effect of emodin combined with ALA-PDT on HPV-associated tumours invivo, we established an animal xenograft model by subcutaneously inoculating mice with SiHa cells (n = 4). The results showed that the combination of emodin and ALA-PDT significantly inhibited the expression of VEGFA to inhibit angiogenesis (p < 0.001), thus showing an inhibitory effect on tumour (p < 0.001). Furthermore, we determined that the mechanism underlying the decrease in VEGFA expression after emodin combined with ALA-PDT in CA may be attributed to the promotion of SerRS expression (p < 0.001). The combination of emodin and ALA-PDT holds promise as a novel therapeutic target for CA by targeting neovascularization in condyloma tissues.

Consequences of the perivascular niche remodeling for tumoricidal T-cell trafficking into metastasis of ovarian cancer.

The treatment-induced activation level within the perivascular tumor microenvironment (TME) that supports T-cell trafficking and optimal T-cell differentiation is unknown. We investigated the mechanisms by which inflammatory responses generated by tumor-specific T cells delivered to ovarian tumor-bearing mice alone or after oncolytic vaccinia virus-driven immunogenic cancer cell death affect antitumor efficacy. Analyses of the perivascular TME by spatially resolved omics technologies revealed reduced immunosuppression and increased tumoricidal T-cell trafficking and function after moderate inflammatory responses driven by a CXCR4 antagonist-armed oncolytic virus. Neither weak nor high inflammation created a permissive TME for T-cell trafficking. Notably, treatment-mediated differences in T-cell effector programs acquired within the perivascular TME contrasted with comparable antigenic priming in the tumor-draining lymph nodes regardless of the activation mode of antigen-presenting cells. These findings provide new insights into combinatorial treatment strategies that enable tumor-specific T cells to overcome multiple barriers for enhanced trafficking and control of tumor growth. .

Abstract A047: Fibroblast-specific IL1 receptor inhibition reprograms the inflammatory stroma to overcome the immunosuppressive tumor microenvironment in pancreatic cancer

Abstract OBJECTIVE: KRAS-driven inflammatory signaling in pancreatic ductal adenocarcinoma (PDAC) promotes cancer-associated fibroblast (CAF) polarization and an immunosuppressive tumor microenvironment (iTME), driving therapeutic resistance. IL1α, a downstream product of KRAS signaling, activates the pro-inflammatory CAF (iCAF) phenotype and correlates with worse survival. Using patient and PDAC mouse model single-cell RNA sequencing (scRNAseq) data, we have shown that the IL1 Receptor (IL1R1) is highly enriched in the fibroblast compartment. However, the role of IL1R1 in modulating iCAFs and the iTME remains poorly understood. We hypothesize that CAF-specific disruption of IL1R1 signaling will reprogram cellular components of the PDAC TME to overcome the immunosuppressive milieu and therapeutic resistance. METHODS: The effects of IL1R1 inhibition on iCAF modulation in vivo were determined in Ptf1aCre/+, LSL-KrasG12D/+, Tgfbr2flox/flox (PKT) mice treated with IL1R1 antagonist. To determine if CAF-specific silencing of IL1R1 recapitulates the TME remodeling after IL1R1 inhibition, we generated a fibroblast-specific IL1R1KO mouse model Col1a2Cre/+;Il1r1flox/flox (CAF-Il1r1KO) and orthotopically injected KPC tumor cells for endpoint analysis. Flow cytometry was performed in primary tumors of CAF-Il1r1KO and littermate controls. Functional experiments evaluating myeloid-derived suppressor cell (MDSC) trafficking were performed using ex vivo bone marrow-derived cells (BMDCs) co-cultured with CAF/tumor-conditioned media (CM) with/without IL1R1 inhibition in a transwell system. MDSC contribution to iTME was assessed by co-culturing MDSCs from CAF-Il1r1KO tumors and splenic T cells from naïve C57BL/6 mice. To investigate the effects of IL1R1 deletion in overcoming therapeutic resistance, survival studies in CAF-Il1r1KO mice with chemotherapy were conducted. RESULTS: Treatment of PKT mice with IL1R1 antagonist diminished transcriptional levels of Il6 and Cxcl1, iCAF-associated cytokines, in the CAF compartment. Compared to littermate controls, orthotopic tumors in CAF-Il1r1KO showed significant reduction in tumor weights, increased CD8+ T cell infiltration, and overall reduction in polymorphonuclear (PMN) MDSC trafficking by flow cytometry. Moreover, migration of BMDCs was reduced when co-cultured with CAF/tumor CM and IL1R1 antagonist. In addition, co-culture of MDSCs from CAF-Il1r1KO mice with naïve T cells showed diminished inhibition of T cell functional activity. Chemotherapy treatment of orthotopic tumors in CAF-Il1r1KO mice showed significantly decreased tumor size and improved survival compared to tumors in littermate controls. CONCLUSION: Our findings illustrate a novel mechanism of CAF-specific disruption of IL1R1 signaling inhibiting trafficking of immunosuppressive MDSCs and increased infiltration of cytotoxic CD8+ T cells in the PDAC TME. These data pave the way for novel combinatorial treatment strategies targeting IL1R1 to overcome chemotherapeutic resistance through reprogramming of the stromal compartment in PDAC. Citation Format: Camille Acevedo, Samara Singh, Austin Dosch, Edmond W Box, Iago C Silva, Anna Bianchi, Siddharth Mehra, Haleh Amirian, Andrew Adams, Nagaraj Nagathihalli, Jashodeep Datta, Nipun B Merchant. Fibroblast-specific IL1 receptor inhibition reprograms the inflammatory stroma to overcome the immunosuppressive tumor microenvironment in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr A047.

Research progress in targeting GPRC5D for the treatment of multiple myeloma

Multiple myeloma (MM) is a malignant disease caused by the abnormal clonal proliferation of plasma cells, accounting for 10% of all hematologic cancers. In recent years, with the development and application of targeted drugs, a significant progress has been observed in the treatment methods of MM, but patients still face the challenges of relapse and drug resistance. Moreover, G protein-coupled receptor class C Group 5 member D (GPRC5D) is highly expressed in MM cells independently of B cell maturation antigen (BCMA) and is a highly promising target following BCMA. Aside from emphasizing the therapeutic efficacy and safety of targeting GPRC5D for the treatment of MM, this study also provides a prospective view on the mechanisms of drug resistance and relapse associated with GPRC5D-targeted therapies, as well as the timing of sequential or combined treatment strategies involving the dual targeting of both GPRC5D and BCMA.

Lynch Syndrome-associated Genomic Variants.

Lynch Syndrome, a hereditary disorder characterized by germline mutations in mismatch repair (MMR) genes, is a major contributor to colorectal cancers. It has also been identified in endometrial cancer. Despite the established role of MMR deficiency in tumorigenesis, the specific genomic alterations driving Lynch syndrome-associated endometrial cancer, and their overlap with colorectal cancer, remain incompletely understood. This study aims to fill this gap by performing a detailed comparative analysis of germline and somatic mutations in endometrial cancer within the context of Lynch syndrome. We conducted whole exome sequencing on matched germline and somatic DNA from 13 patients diagnosed with Lynch syndrome-associated endometrial cancer. High-depth sequencing was performed, followed by rigorous bioinformatics analysis to identify and annotate variants, focusing on their potential pathogenicity and relevance to both endometrial and colorectal cancer. Our analysis revealed 1,118 germline and 14,051 somatic variants, with 493 variants common to both. Recurrent pathogenic mutations in MLH1, MSH2, and MSH6 were confirmed, highlighting their critical role in Lynch syndrome. Notably, frequent somatic mutations in the PIK3CA and PTEN genes were identified, implicating the PI3K/AKT/mTOR pathway as a key oncogenic driver in these cancers. Additionally, novel somatic mutations in genes related to the extracellular matrix such as FBN1 and SPARC were uncovered, suggesting a possible unique role in endometrial tumor progression. This study provides new insights into the molecular basis of Lynch syndrome-associated endometrial cancer, emphasizing the overlap in oncogenic pathways with colorectal cancer. The discovery of shared and unique genetic mutations highlights the importance of developing combined treatment strategies and suggests that targeting these specific mutations could improve therapy for patients with Lynch syndrome-associated cancers.

Clinical Outcome of an All Arthroscopic 'Whole Layer' Rotator Cuff Repair Technique with Simultaneous Biceps Tenodesis.

To retrospectively evaluate clinical outcomes, including function and pain, of patients after our all arthroscopic "whole layer" rotator cuff repair technique with simultaneous biceps tenodesis procedure; factors influencing results were also evaluated. Given the frequent association of rotator cuff tear with long head of biceps lesion and the need for effective combined treatment strategies, this study aims to evaluate the efficacy of our technique and compare it with established methods. We hypothesized that our technique would significantly improve function and reduce pain in patients with rotator cuff tears and biceps pathology. This is a retrospective study that included patients older than 20 years who underwent all arthroscopic "whole layer" rotator cuff repair technique with simultaneous biceps tenodesis procedures for concomitant rotator cuff tear and long head biceps pathology, from 2016 to 2020. Patients were evaluated preoperatively and at a minimum of 2 years of follow-up using the American Shoulder and Elbow Surgeons (ASES) and visual analogue scale (VAS) scores paired t-tests were used for analysis and statistical significance was set at p < 0.05(two-tailed). The satisfaction rate and complications were also evaluated. After an average follow-up of 2.3 years, 118 patients demonstrated significant improvement in both the ASES score (from 36.13 to 95.01, p < 0.001) and VAS score (from 6.81 to 0.89, p < 0.001). Ninety-four percent of the patients reported satisfaction with the surgical outcome. No complications related to Popeye deformity, biceps cramping pain, or ipsilateral shoulder reoperation were observed. Factors such as age, sex, body mass index (BMI), smoking status, alcohol consumption, hypertension, and diabetes did not influence the results. Patients showed significant improvement in both the ASES and VAS scores (p < 0.001). At a mean follow-up time of 2.3 years, the all arthroscopic "whole layer" rotator cuff repair technique with simultaneous biceps tenodesis is a therapeutic and efficient procedure. The procedure revealed a satisfactory functional outcome, reduced pain, and minimal complications and reoperations.

Stability enhancement using a new combined casing treatment strategy in an ultra-highly loaded transonic compressor rotor

Low-reaction compressors are promising for achieving high loads but face severe flow instability challenges. This study investigates a low-reaction transonic compressor rotor using casing treatment technologies to control unstable flow dynamics precisely. First, a design integrating self-recirculating and circumferential groove casing treatments near the leading edge is implemented. This design enhances flow capacity at the tip passage inlet. However, it causes a “stall transposition” phenomenon. The unstable flow structures shift from shock-tip leakage vortex interactions at the front to corner separation at the rear. Consequently, the stall mechanism transitions from an end-wall stall to a blade stall. To address this issue, a new casing treatment layout is proposed. Grooves are added after the mid-chord of the initial front casing configuration. This adaptation suppresses emerging unstable flow structures and extends the stall margin by approximately 12.07 %. Detailed flow field analysis shows that the rear grooves effectively reduced the trailing edge separation vortex. They also limit downstream corner separation and mitigate disturbances from tip leakage flows in the rear of the passage.

Phosphorus Dendrimers Co-deliver Fibronectin and Edaravone for Combined Ischemic Stroke Treatment via Cooperative Modulation of Microglia/Neurons and Vascular Regeneration.

The development of new multi-target combination treatment strategies to tackle ischemic stroke (IS) remains to be challenging. Herein, a proof-of-concept demonstration of an advanced nanomedicine formulation composed of macrophage membrane (MM)-camouflaged phosphorous dendrimer (termed as AK137)/fibronectin (FN) nanocomplexes (NCs) loaded with antioxidant edaravone (EDV) to modulate both microglia and neurons for effective IS therapy is showcased. The created MM@AK137-FN/EDV (M@A-F/E) NCs with a mean size of 260nm possess good colloidal stability, sustained EDV release kinetics, and desired cytocompatibility. By virtue of MM decoration, the M@A-F/E NCs can cross blood-brain barrier, act on microglia to exert the anti-inflammatory (AK137 and FN) and antioxidative (FN and EDV) effects in vitro for oxidative stress alleviation, microglia M2 polarization, and reduction of pro-inflammatory cytokine secretion, and act on neuron cells to be anti-apoptotic. In a transient middle cerebral artery occlusion rat model, the developed M@A-F/E NCs can exert enhanced antioxidant/anti-inflammatory/anti-apoptotic therapeutic effects to comprehensively regulate the brain microenvironment and promote vascular regeneration to collaboratively restore the blood flow after ischemia-reperfusion. The designed MM-coated NCs composed of all-active ingredients of phosphorous dendrimers, FN, and EDV that can fully regulate the brain inflammatory microenvironment may expand their application scope in other neurodegenerative diseases.

Acute Phase Peyronie's Disease: Where Do We Stand?

Peyronie's disease (PD) is a common benign condition characterized by superficial fibrosis and scar formation at the tunica albuginea of the penis, eventually leading to penile curvature. It is believed that penile micro-traumas during intercourse and subsequent activation of inflammatory processes constitute the pathogenetic basis of the disease. Routinely, PD is divided into acute and chronic phases, with pain during erection or flaccid state being the hallmark of the former. Surgical intervention should be avoided during the acute phase, as the risk of recurrence or progression of penile deformity during this stage might affect the optimal outcomes of the procedure. During this stage, many conservative treatment options have been suggested, including oral, topical, and intralesional therapies, extracorporeal shock wave therapy (ESWT), and penile traction therapy (PTT). Currently, the optimal treatment consists of a combined treatment strategy with phosphodiesterase type 5 inhibitors (PDE5Is), ESWT for pain management, PTT, and intralesional therapies. Large, well-designed randomized controlled trials (RCTs) are necessary to further elucidate the most efficient treatment option for acute phase PD.

Intranuclear Irradiation Inhibits Solid Tumor Growth by Upregulating Caspase8 and Activating Apoptosis.

Radioimmunotherapy (RIT) is a novel and promising cancer treatment method, with ongoing research focusing on RIT antibody selection, radionuclides, treatment options, and benefited patient groups. As we dive into the mechanisms of tumor biology, a deeper exploration of how RIT affects tumor tissue is needed to provide new ways to improve clinical treatment outcome and patient prognosis. We labeled the anti-PD-L1 monoclonal antibody atezolizumab with iodine-131 (131I), separated and purified the labeled mAb with Sephadex G-25 medium gel filtration resin, and tested product stability. We detected the in vivo activity of 131I-PD-L1 mAb by analyzing its in vivo biodistribution and performing SPECT imaging and then set different treatment groups to study the effect of 131I-atezolizumab on the survival of tumor-bearing mice. Western blot, real-time quantitative PCR, and immunohistochemistry were used to detect the expression level of Caspase8 and Nlrp3 in tumor. TUNEL fluorescence staining was used to detect the apoptosis in the tumor. The radiopharmaceutical molecular probe 131I-atezolizumab showed high stability and in vivo biological activity. The treatment regimen adopted had a positive effect on the survival of tumor-bearing mice. 131I internal irradiation upregulated Caspase8 in tumor and ultimately inhibited solid tumor growth by activating apoptosis pathways. We also found a significant increase in the expression of NLRP3, which plays an important role in the pyroptosis pathway, in tumor. In summary, our data demonstrated that radiopharmaceuticals combined with immunotherapy affected tumor tissue by modulating relevant biological pathways, thereby achieving better antitumor effects compared with single therapy and providing new insights for promoting better patient prognosis and combination treatment strategies.

The recruitment of CD8+ T cells through YBX1 stabilization abrogates tumor intrinsic oncogenic role of MIR155HG in lung adenocarcinoma

Previous studies revealed that MIR155HG possessed an oncogenic role in many types of tumors including lung adenocarcinoma (LUAD), along with higher expression in tumors. However, in our study, we observed a positive correlation between MIR155HG expression and overall survival across different cohorts. The transferred PBMC on the NCG mouse model abrogated the tumor intrinsic oncogenic role of MIR155HG in LUAD. Upregulation of MIR155HG positively correlated with CD8+ T cell infiltration both in vitro and in vivo, as well as LUAD tissues. Mechanistically, we revealed that MIR155HG increased the cytokine CCL5 expression at the transcriptional level, which depended on the interaction between MIR155HG and YBX1 protein, a novel transcription factor of CCL5, resulting in the more protein stability of YBX1 through dampening ubiquitination. Additionally, we also observed that MIR155 could increase PD-L1 expression to hamper the activity of recruited CD8+ T cells, which could be rescued through PD-L1 mAb addition. Finally, we uncovered that patients with high MIR155HG expression had a higher response rate to immunotherapy, and the combination of MIR155HG overexpression and PD-L1 mAb increased the efficacy of PD-L1 mAb. Together, our study provides a novel biomarker and potential combination treatment strategy for patients who received immunotherapy.

The Evaluation of the protective roles of canagliflozin and zinc sulphate on body weight and hepatic histology in diabetic dyslipidemia

The significant increase in diabetes prevalence in the past decade has placed a considerable strain on the global healthcare system, especially in developing nations such as Pakistan. Although current therapy options effectively manage blood glucose levels, their accompanying adverse effects can hinder patient adherence. This study investigates the therapeutic properties of Canagliflozin, a SGLT-2 inhibitor, recognized for its tolerance and supplementary advantages on body weight and blood pressure, when used in combination with Zinc Sulphate. Zinc is acknowledged for its function in the regulation of hyperglycemia and dyslipidemia. The study involved the use of a type-2 diabetic rat model, induced by a high-fat diet and streptozotocin to examine the separate and combined impacts of Canagliflozin and Zinc Sulphate on the liver's histology. A total of forty-eight male Sprague-Dawley rats were separated into six groups and the treatments were delivered for eight weeks. Body weights were observed and histological evaluations of the liver were performed with the NASH-CRN scoring system. The findings exhibited a notable decrease in body weight among the diabetic-induced groups in comparison to the normal control. The combined utilization of Canagliflozin and Zinc Sulphate showed a heightened efficacy in managing diabetes related weight loss and steatosis of liver in the rat model having type-2 diabetes. This indicates a possible combined treatment strategy that should be further investigated to enhance the management of hepatic steatosis in individuals with diabetes. The study also proposes the potential for using a reduced dosage of Canagliflozin in combination with Zinc, so limiting adverse effects.

Tumor Metabolism: A New Field for the Treatment of Glioma.

The clinical treatment of glioma remains relatively immature. Commonly used clinical treatments for gliomas are surgery combined with chemotherapy and radiotherapy, but there is a problem of drug resistance. In addition, immunotherapy and targeted therapies also suffer from the problem of immune evasion. The advent of metabolic therapy holds immense potential for advancing more efficacious and tolerable therapies against this aggressive disease. Metabolic therapy alters the metabolic processes of tumor cells at the molecular level to inhibit tumor growth and spread, and lead to better outcomes for patients with glioma that are insensitive to conventional treatments. Moreover, compared with conventional therapy, it has less impact on normal cells, less toxicity and side effects, and higher safety. The objective of this review is to examine the changes in metabolic characteristics throughout the development of glioma, enumerate the current methodologies employed for studying tumor metabolism, and highlight the metabolic reprogramming pathways of glioma along with their potential molecular mechanisms. Importantly, it seeks to elucidate potential metabolic targets for glioblastoma (GBM) therapy and summarize effective combination treatment strategies based on various studies.