Therapeutic Approaches Research Articles

Pleiotropic Regulation of PGC-1α in Tumor Initiation and Progression.

Mitochondria are recognized as a central metabolic hub with bioenergetic, biosynthetic, and signaling functions that tightly control key cellular processes. As a crucial component of mitochondrial biogenesis, peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) is involved in regulating various metabolic pathways, including energy metabolism and ROS homeostasis. Recent studies have highlighted the significant role of PGC-1α in tumorigenesis, cancer progression, and treatment resistance. However, PGC-1α exhibits pleiotropic effects in different cancer types, necessitating a more comprehensive and thorough understanding. In this review, we discuss the structure and regulatory mechanisms of PGC-1α, analyze its cellular and metabolic functions, explore its impact on tumorigenesis, and propose potential strategies for targeting PGC-1α. The targeted adjustment of PGC-1α based on the metabolic preferences of different cancer types could offer a hopeful therapeutic approach for both preventing and treating tumors.

Microencapsulation of Origanum heracleoticum L. and Thymus vulgaris L. essential oils – novel strategy to combat multi-resistant Acinetobacter baumannii

Within the global rise of antimicrobial resistance enhanced by the COVID-19 pandemic, where Acinetobacter baumannii has been distinguished as an emerging multi-resistant pathogen, essential oils, become the focus of novel therapeutic approaches. Hypothesizing that encapsulated Origanum heracleoticum L. and Thymus vulgaris L. essential oils could express multi-target approach against A. baumannii, this study aimed to develop microencapsulated systems with optimal technological qualities using 2-hydroxypropyl-β-cyclodextrin as a carrier, and to evaluate their pharmacological potential against A. baumannii, and their morphological and physicochemical characteristics, safety and stability profiles. The highest yield and encapsulation efficiency were obtained with 1:10 essential oil to carrier, and 1.5:10 carrier to water w/w ratios. The formation of inclusion complexes was confirmed by Fourier Transform Infrared Spectroscopy. Both microencapsulates achieved improved homogeneity, particle surface, and thermal stability compared with the pure carrier. Dominant bioactive compounds (carvacrol and p-cymene in O. heracleoticum essential oil, and thymol and p-cymene in T. vulgaris essential oil) remained the most abundant after encapsulation. While non-encapsulated essential oils revealed similar antimicrobial activity towards clinical A. baumannii isolates obtained from COVID-19 patients, encapsulated O. heracleoticum essential oil inhibited the bacterial growth at lower concentrations than T. vulgaris essential oil microencapsulate. All samples significantly reduced the formation of A. baumannii biofilm, for at least 53.90% towards the most infective isolate according to the Caenorhabditis elegans assay. Further, in silico molecular docking study revealed strong interaction pattern of carvacrol and thymol with the outer membrane protein A, which is the main factor for the A. baumannii biofilm formation. Cytotoxicity investigation on human lung A549 cells showed high survival rate in the presence of all tested concentrations, and the stability study revealed notable preservation of the bioactives’ content and pharmacological potential. Altogether, microencapsulated essential oils exhibited a multi-target approach towards A. baumannii, with satisfactory preserving capability during storage.

GASTRIC GASTROINTESTINAL STROMAL TUMOR WITH SUCCINATE DEHYDROGENASE B DEFICIENCY: CLINICAL CASE

Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors found in the gastrointestinal tract, constituting a diverse group of c-Kit positive mesenchymal (stromal or connective tissue) tumors. Their development is primarily associated with mutations in the c-Kit proto-oncogene, leading to structural alterations in the type III transmembrane tyrosine kinase receptor (Kit). This receptor is crucial for regulating mitotic activity and cell differentiation. The activation of the Kit-receptor in tumor cells is identified through the expression of the immunohistochemical marker CD 117 (tyrosine kinase receptor protein), with approximately 80-90% of GISTs testing positive for CD 117. The objective of our study is to improve the diagnosis and treatment of gastrointestinal stromal tumors. The clinical case underscores the challenge of diagnosing gastrointestinal stromal tumors (GISTs) due to the absence of specific and definitive symptoms. In this instance, only radical surgical intervention facilitated an accurate diagnosis. Given the location of the tumor in the pyloric part of the gastric submucosal layer, a reliable biopsy during video esophagogastroduodenoscopy was unfeasible, as the gastric mucosa above the tumor appeared unaffected. Consequently, surgery with complete tumor excision and subsequent pathohistological and immunohistochemical analysis emerged as the primary diagnostic and therapeutic approach. These investigations confirmed the presence of a gastrointestinal stromal tumor of the stomach with succinate dehydrogenase B deficiency. In approximately 80% of GIST cases, succinate dehydrogenase deficiency plays a pivotal role. The absence of succinate dehydrogenase disrupts the Krebs cycle, leading to an accumulation of succinate, an oncometabolite that fuels carcinogenesis. Such tumors exhibit distinctive clinical characteristics, prognostic outcomes, and responsiveness to targeted therapies. Succinate dehydrogenase deficiency can arise from mutations or epigenomic alterations affecting gene expression. Notably, mutations or epigenomic disruptions in any succinate dehydrogenase subunit inevitably result in the loss of subunit B expression.

Dual targeting negative enrichment strategy for highly sensitive and purity detection of CTCs

Circulating tumor cells (CTCs) have significant clinical value in early tumor detection, dynamic monitoring and immunotherapy. CTC detection stands out as a leading non-invasive approach for tumor diagnostics and therapeutics. However, the high heterogeneity of CTCs and the occurrence of epithelial-mesenchymal transition (EMT) during metastasis pose challenges to methods relying on EpCAM-positive enrichment. To address these limitations, a method based on negative enrichment of CTCs using specific leukocyte targets has been developed. In this study, aiming to overcome the low purity associated with immunomagnetic beads targeting solely the leukocyte common antigen CD45, we introduced CD66b-modified immunomagnetic beads. CD66b, a specific target for neutrophils with abundant residues, was chosen as a complementary approach. The process involved initial collection of nucleated cells from whole blood samples using density gradient centrifugation. Subsequently, magnetically labeled leukocytes were removed by magnetic field, enabling the capture of CTCs with higher sensitivity and purity while retaining their activity. Finally, we selected 20 clinical blood samples from patients with various cancers to validate the effectiveness of this strategy, providing a new generalized tool for the clinical detection of CTCs.

Effectiveness of Ceftazidime/Avibactam treatment for infections caused by Klebsiella pneumoniae Carbapenemase (KPC), a 30-day mortality perspective. Comparison of results with control groups treated with other antibiotics

Introduction: Infections caused by Klebsiella pneumoniae carbapenemase (KPC) pose a significant clinical challenge due to increasing antibiotic resistance. This study analyzes the effectiveness of ceftazidime/avibactam treatment for KPC infections, focusing on 30-day mortality and comparing results with control groups treated with different antibiotics. Material and methods: We conducted a retrospective analysis of six cohort studies, comparing thirty-day mortality in patients treated with ceftazidime/avibactam with control groups using other antibiotics. The studies included patients infected with KPC, and the analysis focused on therapeutic effectiveness. Aim of the study: The aim of the study is to compare the results in terms of 30-day mortality in groups treated with ceftazidime/avibactam compared to control groups using different antibiotics. Conclusions: Data analysis from various studies revealed varied 30-day mortality outcomes in groups treated with ceftazidime/avibactam compared to control groups using different antibiotics. Ceftazidime/avibactam proved to be more effective in all studies, reducing mortality rates compared to other treatment regimens. We emphasize that emerging antibiotic resistance, especially in the case of KPC, requires a comprehensive therapeutic approach. Despite promising ceftazidime/avibactam results, factors such as overall patient health and treatment delays may influence final therapy outcomes. We also highlight controversies regarding combination therapy vs. monotherapy, necessitating further research. Our work underscores the importance of monitoring the effectiveness of KPC infection treatment and exploring new therapeutic strategies. Further clinical studies are essential to develop a fuller understanding and optimal therapeutic protocols in the face of the growing antibiotic resistance problem.

Microglia, Trem2, and Neurodegeneration.

Microglia are a specialized type of neuroimmune cells that undergo morphological and molecular changes through multiple signaling pathways in response to pathological protein aggregates, neuronal death, tissue injury, or infections. Microglia express Trem2, which serves as a receptor for a multitude of ligands enhancing their phagocytic activity. Trem2 has emerged as a critical modulator of microglial activity, especially in many neurodegenerative disorders. Human TREM2 mutations are associated with an increased risk of developing Alzheimer disease (AD) and other neurodegenerative diseases. Trem2 plays dual roles in neuroinflammation and more specifically in disease-associated microglia. Most recent developments on the molecular mechanisms of Trem2, emphasizing its role in uptake and clearance of amyloid β (Aβ) aggregates and other tissue debris to help protect and preserve the brain, are encouraging. Although Trem2 normally stimulates defense mechanisms, its dysregulation can intensify inflammation, which poses major therapeutic challenges. Recent therapeutic approaches targeting Trem2 via agonistic antibodies and gene therapy methodologies present possible avenues for reducing the burden of neurodegenerative diseases. This review highlights the promise of Trem2 as a therapeutic target, especially for Aβ-associated AD, and calls for more mechanistic investigations to understand the context-specific role of microglial Trem2 in developing effective therapies against neurodegenerative diseases.

Immunotherapy in Alzheimer's disease: focusing on the efficacy of gantenerumab on amyloid-β clearance and cognitive decline.

Gantenerumab, a human monoclonal antibody (mAb), has been thought of as a potential agent to treat Alzheimer's disease (AD) by specifically targeting regions of the amyloid-β (Aβ) peptide sequence. Aβ protein accumulation in the brain leads to amyloid plaques, causing neuroinflammation, oxidative stress, neuronal damage, and neurotransmitter dysfunction, thereby causing cognitive decline in AD. Gantenerumab involves disrupting Aβ aggregation and promoting the breakdown of larger Aβ aggregates into smaller fragments, which facilitates the action of Aβ-degrading enzymes in the brain, thus slowing down the progression of AD. Moreover, Gantenerumab acts as an opsonin, coating Aβ plaques and enhancing their recognition by immune cells, which, combined with its ability to improve the activity of microglia, makes it an intriguing candidate for promoting Aβ plaque clearance. Indeed, the multifaceted effects of Gantenerumab, including Aβ disaggregation, enhanced immune recognition, and improved microglia activity, may position it as a promising therapeutic approach for AD. Of note, reports suggest that Gantenerumab, albeit its capacity to reduce or eliminate Aβ, has not demonstrated effectiveness in reducing cognitive decline. This review, after providing an overview of immunotherapy approaches that target Aβ in AD, explores the efficacy of Gantenerumab in reducing Aβ levels and cognitive decline.

Personalized Nanovaccines Enhance Lymph Node Accumulation and Reprogram the Tumor Microenvironment for Improved Photodynamic Immunotherapy.

Tumor immunotherapy has emerged as an efficacious therapeutic approach that mobilizes the patient's immune system to achieve durable tumor suppression. Here, we design a photodynamic therapy-motivated nanovaccine (Dex-HDL/ALA-Fe3O4) co-delivering 5-aminolevulinic acid and Fe3O4 nanozyme that demonstrate a long-term durable immunotherapy strategy. After vaccination, the nanovaccine exhibits obvious tumor site accumulation, lymph node homing, and specific and memory antitumor immunity evocation. Upon laser irradiation, Dex-HDL/ALA-Fe3O4 effectively generates reactive oxygen species at the tumor site not only to induce the immunogenic cell death-cascade but also to trigger the on-demand release of full types of tumor antigens. Intriguingly, Fe3O4 nanozyme-catalyzed hydrogen peroxide generated oxygen for alleviating tumor hypoxia and modifying the inhibitory tumor microenvironment, thereby exhibiting remarkable potential as a sensitizer. The intravenous administration of nanovaccines in diverse preclinical cancer models has demonstrated remarkable tumor regression and inhibition of postoperative tumor recurrence and metastasis, thereby enabling personalized treatment strategies against highly heterogeneous tumors.

Coordination-Driven Self-Assembly of Metal Ion-Antisense Oligonucleotide Nanohybrids for Chronic Bacterial Infection Therapy.

Bacterial infection poses a significant challenge to wound healing and skin regeneration, leading to substantial economic burdens on patients and society. Therefore, it is crucial to promptly explore and develop effective methodologies for bacterial infections. Herein, we propose a novel approach for synthesizing nanostructures based on antisense oligonucleotides (ASOs) through the coordination-driven self-assembly of Zn2+ with ASO molecules. This approach aims to provide effective synergistic therapy for chronic wound infections caused by Staphylococcus aureus (S. aureus). The resulting hybrid nanoparticles successfully preserve the structural integrity and biological functionalities of ASOs, demonstrating excellent ASO encapsulation efficiency and bioaccessibility. In vitro antibacterial experiments reveal that Zn-ASO NPs exhibit antimicrobial properties against Escherichia coli, Staphylococcus aureus, and Bacillus subtilis. This antibacterial ability is attributed to the high concentration of metal zinc ions and the generation of high levels of reactive oxygen species. Additionally, the ftsZ-ASO effectively inhibits the expression of the ftsZ gene, further enhancing the antimicrobial effect. In vivo antibacterial assays demonstrate that the Zn-ASO NPs promote optimal skin wound healing and exhibit favorable biocompatibility against S. aureus infections, resulting in a residual infected area of less than 8%. This combined antibacterial strategy, which integrates antisense gene therapy and metal-coordination-directed self-assembly, not only achieves synergistic and augmented antibacterial outcomes but also expands the horizons of ASO coordination chemistry. Moreover, it addresses the gap in the antimicrobial application of metal-coordination ASO self-assembly, thereby advancing the field of ASO-based therapeutic approaches.

Open questions on basal insulin therapy in T2D: a Delphi consensus.

The revolution in the therapeutic approach to type 2 diabetes (T2D) requires a rethinking of the positioning of basal insulin (BI) therapy. Given the considerable number of open questions, a group of experts was convened with the aim of providing, through a Delphi consensus method, practical guidance for doctors. A group of 6 experts developed a series of 29 statements on: the role of metabolic control in light of the most recent guidelines; BI intensification strategies: (1) add-on versus switch; (2) inertia in starting and titrating; (3) free versus fixed ratio combination; basal-bolus intensification and de-intensification strategies; second generation analogues of BI (2BI). A panel of 31 diabetologists, by accessing a dedicated website, assigned each statement a relevance score on a 9-point scale. The RAND/UCLA Appropriateness Method was adopted to assess the existence of disagreement among participants. Panelists showed agreement for all 29 statements, of which 26 were considered relevant, one was considered not relevant and two were of uncertain relevance. Panelists agreed that the availability of new classes of drugs often allows the postponement of BI and the simplification of therapy. It remains essential to promptly initiate and titrate BI when required. BI should always, unless contraindicated, be started in addition to, and not as a replacement, for ongoing treatments with cardiorenal benefits. 2BIs should be preferred for their pharmacological profile, greater ease of self-titration and flexibility of administration. In a continuously evolving scenario, BI therapy still represents an important option in the management of T2D patients.

SEX DIFFERENCES IN THE CORONARY SYSTEM OF THE HUMAN HEART

The aim of this study is to investigate sex differences in the coronary system of the heart, considering all relevant consequence, and to compile and analyze the gathered data. Materials and Methods. The authors independently conducted a literature search and selection process using the PubMed database for the review, followed by the generalization of the obtained data. Results. Women exhibit a higher propensity than men for certain cardiovascular diseases, including persistent angina, non-obstructive coronary heart disease, coronary microvascular dysfunction, spontaneous coronary artery dissection, stress cardiomyopathy, and heart failure with preserved ejection fraction (HFpEF). In comparison to men, women typically present with elevated rates of underlying comorbidities, encompassing not only advanced age but also hypertension, diabetes mellitus, obesity, chronic renal failure, peripheral vascular disease, HFpEF, and inflammatory conditions like rheumatoid arthritis. Many of these conditions are linked to diffuse atherosclerosis and microvascular ischemia, with notable parallels between non-obstructive coronary heart disease and coronary microvascular dysfunction. Special attention is paid to patients sharing an increased risk of coronary heart disease events, which is consistent between women and men, except for those with severe coronary flow reserve (CFR) impairment, where women demonstrate an even higher risk. In particular, in cases where CFR impairment is not attributable to obstructive coronary heart disease (precluding revascularization to mitigate cardiovascular risk), there may be justification for a novel therapeutic approach for systemic coronary heart disease management. Cases of severe coronary microvascular dysfunction, often concurrent with non-obstructive coronary heart disease, may indicate a shared mechanism influencing coronary heart disease risk in both genders. This mechanism might involve inflammation, endothelial dysfunction, and heightened cardiomyocyte oxygen demand, culminating in microvascular ischemia, myocardial injury, and compromised cardiac function. Conclusions. Enhanced comprehension of the interplay between coronary vasomotor dysfunction and the concomitance of coronary heart disease with other conditions, such as insulin resistance and heart failure, could foster the advancement of novel systemic treatments aimed at leveraging “complete revascularization” more effectively.

Targeting glutamine metabolism improves sarcoma response to radiation therapy in vivo

Diverse tumor metabolic phenotypes are influenced by the environment and genetic lesions. Whether these phenotypes extend to rhabdomyosarcoma (RMS) and how they might be leveraged to design new therapeutic approaches remains an open question. Thus, we utilized a Pax7Cre-ER-T2/+; NrasLSL-G12D/+; p53fl/fl (P7NP) murine model of sarcoma with mutations that most frequently occur in human embryonal RMS. To study metabolism, we infuse 13C-labeled glucose or glutamine into mice with sarcomas and show that sarcomas consume more glucose and glutamine than healthy muscle tissue. However, we reveal a marked shift from glucose consumption to glutamine metabolism after radiation therapy (RT). In addition, we show that inhibiting glutamine, either through genetic deletion of glutaminase (Gls1) or through pharmacological inhibition of glutaminase, leads to significant radiosensitization in vivo. This causes a significant increase in overall survival for mice with Gls1-deficient compared to Gls1-proficient sarcomas. Finally, Gls1-deficient sarcomas post-RT elevate levels of proteins involved in natural killer cell and interferon alpha/gamma responses, suggesting a possible role of innate immunity in the radiosensitization of Gls1-deficient sarcomas. Thus, our results indicate that glutamine contributes to radiation response in a mouse model of RMS.

Neuronopathic Gaucher disease: Rare in the West, common in the East.

Gaucher disease (GD) stands as one of the most prevalent lysosomal disorders, yet neuronopathic GD (nGD) is an uncommon subset characterized by a wide array of clinical manifestations that complicate diagnosis, particularly when neurological symptoms are understated. nGD may manifest as the acute neuronopathic type, or GD type 2 (GD2), either prenatally or within the first weeks to months of life, whereas GD type 3 (GD3) symptoms may emerge at any point during childhood or occasionally in adolescence. The clinical presentation encompasses severe systemic involvement to mild visceral disease, often coupled with a spectrum of progressive neurological signs and symptoms such as cognitive impairment, ataxia, seizures, myoclonus, varying degrees of brainstem dysfunction presenting with stridor, apneic episodes, and/or impaired swallowing. This manuscript aims to provide a comprehensive review of the incidence, distinctive presentations, and diverse clinical phenotypes of nGD across various countries and regions. It will explore the natural history of the neurodegenerative process in GD, shedding light on its various manifestations during infancy and childhood, and offer insights into the diagnostic journey, the challenges faced in the clinical management, and current and investigative therapeutic approaches for GD's neurological variants.

Unraveling the Microbiome–Human Body Axis: A Comprehensive Examination of Therapeutic Strategies, Interactions and Implications

This review scrutinizes the intricate interplay between the microbiome and the human body, exploring its multifaceted dimensions and far-reaching implications. The human microbiome, comprising diverse microbial communities inhabiting various anatomical niches, is increasingly recognized as a critical determinant of human health and disease. Through an extensive examination of current research, this review elucidates the dynamic interactions between the microbiome and host physiology across multiple organ systems. Key topics include the establishment and maintenance of microbiota diversity, the influence of host factors on microbial composition, and the bidirectional communication pathways between microbiota and host cells. Furthermore, we delve into the functional implications of microbiome dysbiosis in disease states, emphasizing its role in shaping immune responses, metabolic processes, and neurological functions. Additionally, this review discusses emerging therapeutic strategies aimed at modulating the microbiome to restore host–microbe homeostasis and promote health. Microbiota fecal transplantation represents a groundbreaking therapeutic approach in the management of dysbiosis-related diseases, offering a promising avenue for restoring microbial balance within the gut ecosystem. This innovative therapy involves the transfer of fecal microbiota from a healthy donor to an individual suffering from dysbiosis, aiming to replenish beneficial microbial populations and mitigate pathological imbalances. By synthesizing findings from diverse fields, this review offers valuable insights into the complex relationship between the microbiome and the human body, highlighting avenues for future research and clinical interventions.

Current Knowledge on Nail Involvement in Autoimmune Bullous Disorders

<b><i>Background:</i></b> There are few studies, mainly case reports, on the involvement of the nail unit in autoimmune bullous disorders. <b><i>Summary:</i></b> Nail involvement in autoimmune bullous disorders is a significant clinical phenomenon, marked by a range of manifestations, most often not presenting with blisters like on the skin but rather with alterations of the nail unit such as paronychia, onychomadesis, or onycholysis. This involvement is particularly notable due to the unique immunological features of the nail unit, including the expression of various antigens and the presence of Langerhans cells. Conditions like pemphigus vulgaris, bullous pemphigoid, epidermolysis bullosa acquisita, linear IgA disease, and bullous systemic lupus erythematosus can lead to nail abnormalities. The prevalence of nail manifestations varies according to the disorder, and diagnosis often relies on histopathological and immunofluorescence testing. Nail involvement correlates with disease severity and duration, sometimes serving as a herald sign. Further research is needed to guide therapeutic approaches for nail involvement in autoimmune bullous diseases. <b><i>Key Messages:</i></b> Nail involvement in autoimmune bullous nail disorders may be confusing as there are almost never bullae. One should keep the diagnosis in mind when facing an atypical paronychia.

GPR30 improved subarachnoid hemorrhage induced blood-brain barrier dysfunction by activating PI3K/Akt and Nrf2/HO-1 pathways.

The blood-brain barrier (BBB) plays a critical role in the development and outcome of subarachnoid hemorrhage (SAH). This study focuses on the potential mechanism by which GPR30 affects the BBB after SAH. A rat SAH model was established using an intravascular perforation approach. G1 (GPR30 agonist) was administered to investigate the mechanism of BBB damage after SAH. Brain water content, western blotting, Evans blue leakage, and immunofluorescence staining were performed. Brain microvascular endothelial cells were induced by hemin to establish SAH model in vitro. By adding LY294002 (a PI3K blocker) and ZnPP IX (an HO-1 antagonist), the mechanism of improving BBB integrity through the activation of GPR30 was studied. In vivo, GPR30 activation improved BBB disruption, as evidenced by decreased cerebral edema, downregulated Albumin expression, and reduced extravasation of Evans blue and lgG after G1 administration in SAH rats. Moreover, SAH downregulated the levels of tight junction (TJ) proteins, while treatment with G1 reversed the effect of SAH. The protective effect of G1 on BBB integrity in vitro was consistent with that in vivo, as evidenced by G1 reducing the impact of hemin on TEER value, dextran diffusivity, and TJ protein levels in brain microvascular endothelial cells. In addition, G1 activated the PI3K/AKT and Nrf2/HO-1 pathways both in vivo and in vitro. Furthermore, the administration of LY294002 and ZnPP IX partially reversed the protective effect of G1 on BBB integrity in hemin-stimulated cells. These findings provide valuable insights for potential treatments for SAH. NEW & NOTEWORTHY We demonstrated that the activation of GPR30, at least partly through the PI3K/AKT and Nrf2/HO-1 pathways, alleviated BBB damage both in vivo and in vitro. This study introduced a novel therapeutic approach for protecting the BBB after SAH.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) complicated with intestinal obstruction and perforation.

We report the case of a patient who comes to the emergency department with abdominal pain, oral intolerance and bloody stools, being diagnosed with intestinal obstruction secondary to a jejunal tumor with contained perforation. A laparotomy was performed with resection of the jejunal tumor and taking biopsies from lesions with similar characteristics in the rest of the small bowel compatible with monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL). The monomorphic epitheliotropic intestinal T-cell lymphoma is a rare intestinal tumor with a poor prognosis that is characterized by the proliferation of intraepithelial lymphocytes. The abdominal symptoms are nonspecific and the known major complications are intestinal perforation and obstruction. There is no standard therapeutic approach, being a combination of surgical resection, chemotherapy and autologous stem cell transplant.

Single-center experience of patients with plasma cell leukemia in the era of new therapeutics.

Plasma cell leukemia (PCL) can occur de novo as primary PCL (pPCL), or in patients with prior diagnosis of multiple myeloma (MM) as secondary PCL (sPCL). In 2021, the diagnostic criteria have been revised, establishing a new cut-off of ≥ 5 % plasma cells in the peripheral blood. Lacking specific clinical trials, PCL is treated similarly to MM, however outcome for patients with PCL remains poor. Here, we report outcomes for patients with pPCL and sPCL in the era of novel agents. We performed a retrospective analysis and identified 19 patients (11 pPCL, 8 sPCL) who have been treated for PCL between 2010 and 2022 at University Hospital Essen. Patients with pPCL had a median overall survival (OS) of 37.8 months (95% CI: [15.4; 52.3] months) from diagnosis, with a median time to next treatment (TTNT) of 18.4 [2.0; 22.9] months. All patients were treated with a proteasome- inhibitor (PI)-based induction therapy and the majority was consolidated with an autologous stem cell transplantation (SCT). Five of these patients received a tandem transplantation. Patients with sPCL had a median OS of only 1.5 months after diagnosis of PCL. Only one patient achieved a remission with daratumumab and subsequent allogenic SCT. With our study, we add evidence for a PI-based induction therapy followed by a consolidating autologous stem cell transplantation for patients with pPCL and give further evidence that a tandem transplant concept might be beneficial. The diagnosis of sPCL remains devasting and needs new therapeutic approaches.

Fistulising skin metastases in Crohn’s disease: a case report and review of the literature

BackgroundMetastatic Crohn’s disease is a rare disorder characterized by various granulomatous skin lesions that occur independently of gastrointestinal tract involvement. However, currently there is no standardized care or specific treatment. Therapeutic approaches include immunosuppressive agents, such as corticosteroids, azathioprine, and monoclonal antibodies targeting inflammatory cytokines like tumor necrosis factor (TNF).Case presentationWe present a case of a 29-year-old western European woman with significant blind ending abdominal subcutaneous fistulas and abscesses, who sought evaluation in the dermatology department. Histological examination revealed multiple epithelioid cell granulomas. There was no evidence of infectious or rheumatologic diseases such as sarcoidosis. The tentative diagnosis was metastatic Crohn’s disease, which was not related to an intestinal manifestation of the disease. The patient responded to infliximab but had to discontinue it due to an allergic reaction. Subsequent adalimumab treatment failed to induce clinical remission; thus, therapy was switched to ustekinumab, resulting in a positive response. Written informed consent for publication of their clinical details and clinical images was obtained from the patient.For our study more than 1600 publications were screened for cases of metastatic Crohn’s disease on PubMed database. 59 case reports with 171 patients were included in the analysis and evaluated for localization, diagnostic and therapeutic approaches, and complications and were summarized in this review.ConclusionThe successful ustekinumab treatment of a patient with metastatic Crohn's disease underscores the potential of this minimally investigated therapeutic option, highlighting the need for future treatment guidelines given the increasing prevalence of such cases.

Exploring new avenues of health protection: plant-derived nanovesicles reshape microbial communities.

Symbiotic microbial communities are crucial for human health, and dysbiosis is associated with various diseases. Plant-derived nanovesicles (PDNVs) have a lipid bilayer structure and contain lipids, metabolites, proteins, and RNA. They offer unique advantages in regulating microbial community homeostasis and treating diseases related to dysbiosis compared to traditional drugs. On the one hand, lipids on PDNVs serve as the primary substances that mediate specific recognition and uptake by bacteria. On the other hand, due to the multifactorial nature of PDNVs, they have the potential to enhance growth and survival of beneficial bacterial while simultaneously reducing the pathogenicity of harmful bacteria. In addition, PDNVs have the capacity to modulate bacterial metabolism, thus facilitating the establishment of a harmonious microbial equilibrium and promoting stability within the microbiota. These remarkable attributes make PDNVs a promising therapeutic approach for various conditions, including periodontitis, inflammatory bowel disease, and skin infection diseases. However, challenges such as consistency, isolation methods, and storage need to be addressed before clinical application. This review aims to explore the value of PDNVs in regulating microbial community homeostasis and provide recommendations for their use as novel therapeutic agents for health protection.