Search

Klebsiella pneumoniae strains that are resistant to multiple drugs (KPMDRs), which are often acquired in hospital settings and lead to healthcare-associated infections, pose a serious public health threat, as does hypervirulent K. pneumoniae (hvKp), which can also cause serious infections in otherwise healthy individuals. The widespread and often unnecessary use of antibiotics seen during the recent COVID-19 pandemic has exacerbated the challenges posed by antibiotic resistance in clinical settings. There is growing concern that hypervirulent (hvKp) strains may acquire genes that confer antimicrobial resistance, thus combining an MDR profile with their increased ability to spread to multiple body sites, causing difficult-to-treat infections. This study aimed to compare resistance and virulence profiles in KPC-3-producing K. pneumoniae isolates collected over four years (2020-2023). A genome-based surveillance of all MDR CRE- K. pneumoniae was used to identify genetic differences and to characterize the virulence and resistance profiles. Our results provide a picture of the evolution of resistance and virulence genes and contribute to avoiding the possible spread of isolates with characteristics of multi-drug resistance and increased virulence, which are thought to be one of the main global challenges to public health, within our hospital.

Transient receptor potential ankyrin 1 (TRPA1) channels are expressed on the surface of different cell types, including immune cells. However, TRPA1's role in the context of innate and adaptive immune responses has not been fully elucidated so far. In this study, we aimed at investigating the expression and function of TRPA1 channels on NK cells. Among NK cells, TRPA1 was highly expressed by the CD56 dim CD16 + subpopulation, but not by CD56 bright CD16 - cells, as detected by FACS. TRPA1 activation with the potent ligand allyl isothiocyanate (AITC) induces intracellular calcium flux in CD56 dim CD16 + cells, which was prevented by the TRPA1 antagonist HC-030031. AITC treatment increased the membrane around NKp44 and strongly decreased CD16 and CD8 expression, while CD158a, CD159a, NKG2d, NKp46 were substantially unaffected. Importantly, AITC increased the granzyme production and CD107 expression and increased NK cell-mediated cytotoxicity towards the K562 cell line and two different melanoma cell lines. In parallel, TRPA1 activation also plays regulatory roles by affecting the survival of NK cells to limit uncontrolled and prolonged NK cell-mediated cytotoxicity. Our results indicate that the activation of TRPA1 is an important regulatory signal for NK cells, and agonists of TRPA1 could be used to strengthen the tumor response of the immune system.

PI3K pathway plays a crucial role in dendritic cells (DCs) functions, as it regulates different cellular processes, such as maturation and cytokines production. However, the specific role of PI3K p110δ isoform in human DCs has not been thoroughly addressed. In this study, we analyze the effects of seletalisib, a potent and specific inhibitor of PI3K p110δ, on phenotype and antigen-presenting functions of monocyte-derived DCs undergone maturation via LPS. Seletalisib treatment reduced membrane HLA-DR as well as CD83 and CD40 costimulatory molecules, whereas CD80 and CD86 expression was only partially affected. Additionally, DCs cultures showed reduced TNF-α, IL-10, and IL-12 and increased IL-23 secretion levels. This resulted in a reduced capacity of DCs to prime allogeneic T cells, with a strong decrease of Th1 differentiation. On the other hand, PI3K p110δ inhibitor seletalisib increased CXCR4 and CCR7 expression and augmented the DCs migration toward CCL19 and CXCL12 ligands. At molecular level, inhibition of PI3K p110δ isoform by seletalisib significantly down-regulated the phosphorylation of AKT and other downstream signaling molecules, such as ribosomal protein S6, 4E-BP1, and NF-κB p65. In contrast, seletalisib did not affect p38 MAP kinase phosphorylation or TLR-associated adapter molecule TIRAP in DCs. Our results indicate that PI3K p110δ can serve as an important regulatory signal for DCs, and selective inhibition of PI3K p110δ isoform by seletalisib could be used for the prevention of exaggerated and harmful immune responses occurring in pathologic conditions, such as autoimmune disorders., (©2022 Society for Leukocyte Biology.)

Besides their primary role in hemostasis, platelets contain a plethora of immunomodulatory molecules that profoundly affect the entire process of wound repair. Therefore, platelet derivatives, such as platelet-rich plasma or platelet lysate, have been widely employed with promising results in the treatment of chronic wounds. Platelet derivatives provide growth factors, cytokines, and chemokines targeting resident and immigrated cells belonging to the innate and adaptive immune system. The recruitment and activation of neutrophils and macrophages is critical for pathogen clearance in the early phase of wound repair. The inflammatory response begins with the release of cytokines, such as TGF-β, aimed at damping excessive inflammation and promoting the regenerative phase of wound healing. Dysregulation of the immune system during the wound healing process leads to persistent inflammation and delayed healing, which ultimately result in chronic wound. In this review, we summarize the role of the different immune cells involved in wound healing, particularly emphasizing the function of platelet and platelet derivatives in orchestrating the immunological response.

Background: Platelet lysate (PL) contains a cocktail of growth factors and cytokines that promote tissue repair and regeneration. In vitro studies have shown that PL may affect the reparative function of keratinocytes and fibroblasts, but little is known about the effect of PL on immune cells involved in wound healing., Objectives: To analyse the effects of PL on T cells involved in the wound repair process., Materials and Methods: The effect of PL on T cell proliferation, activation, and cytokine production was measured by ELISA and cytofluorometry and regulatory function based on cytofluorometry and Foxp3 RNA expression. Using an in vitro model of wound healing, we investigated the effect of PL-treated T cells on fibroblast proliferation and production of fibronectin and type-1 collagen as well as keratinocyte migration., Results: PL induced T lymphocyte proliferation and CD69 expression, and promoted a transient upregulation of IFN-γ and TNF-α. However, later on, PL enhanced the number of CD25 + T cells releasing TGF-β and expressing Foxp3 RNA, which was accompanied by a suppression in the level of type 1 cytokines. In the in vitro model, supernatants of PL-treated T cells positively affected the reparative capacity of human keratinocytes and induced fibroblast proliferation and production of fibronectin and type-1 collagen., Conclusion: These results indicate that PL temporally regulates T cells during the healing process, enhancing protective cytokines in the early phase, followed by a prominent expansion of TGF-β + T regulatory cells that promote tissue regeneration and dampen the inflammatory response to prevent excessive tissue damage.

IL-17 and IL-22 are tissue-signaling cytokines that favor protection and regeneration of barrier organs such as the skin, lung, and gastrointestinal system. Both cytokines share cellular sources, signaling pathways, and functional aspects; however, taking a closer look they differ, e.g. in their pro-inflammatory or regenerative potential. An imbalance of the carefully orchestrated tissue-signaling system might result in autoimmune diseases, promote cancer growth, or predispose to infectious diseases. This review highlights recent understandings in cellular sources, signaling mechanisms, physiologic as well as pathogenic role of the double-faceted cytokines IL-17 and IL-22., (© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

KRAS mutations are the most common oncogenic event in colorectal cancer (CRC) progression and their occurrence is associated with lack of response to anti epidermal growth factor receptor (EGFR) targeted therapies. Using preclinical models and patients' samples we recently reported that the emergence of KRAS mutations but also KRAS amplification is associated with acquired resistance to the EGFR inhibitors cetuximab or panitumumab. We reasoned that KRAS amplification may also be responsible for primary resistance to these agents. Furthermore, while the prevalence of KRAS mutations has been well established in CRC, little is known about the frequency of KRAS amplification in large CRC series. We performed a screening of 1,039 CRC samples to assess the prevalence of KRAS amplification in this tumor type and further evaluated the role of this genetic alteration on the sensitivity to anti EGFR therapies. We detected KRAS amplification in 7/1,039 (0.67%) and 1/102 evaluable CRC specimens and cell lines, respectively. KRAS amplification was mutually exclusive with KRAS mutations. Tumors or cell lines harboring this genetic lesion are not responsive to anti-EGFR inhibitors. Although KRAS amplification is an infrequent event in CRC, it might be responsible for precluding response to anti-EGFR treatment in a small proportion of patients., (Copyright © 2013 UICC.)

Biliary dyskinesia is frequently encountered in clinical practice and is characterized by pain during or after meals. The present study was designed to assess the action of hymecromone in patients with motor disorders of the bile ducts. One hundred twenty-three patients (36 men and 87 women) were enrolled in the multicenter double-blind placebo-controlled study. The mean age was 60.3 years +/- 14.2 SD. Diagnosis was dyspepsia in 58 patients, dyskinesia in 59, cholelithiasis in five and hepatopathy in one. The patients were divided into two groups. One group (61 patients) was treated with hymecromone (300 mg tablets at a dosage of 1,200 mg/day, 2 tablets midday and evening) and another group (62 patients) was treated with placebo. Treatment lasted for 14 days. Control of dyspepsia and pain symptoms of biliary origin was more marked and constant with hymecromone than with placebo. By the end of the treatment, patients in the hymecromone group showed a 70.3% reduction in intensity of spontaneous abdominal pain, while the placebo group showed a 43.8% reduction. Hymecromone was well accepted by the patients and judged to be effective by the investigator in 88.5% of patients treated. The possibility of using hymecromone in 300-mg tablets in the treatment of motor disorders of the bile ducts is thus confirmed.