Osteoporotic fractures: an unrecognized adverse event of immune checkpoint inhibitors?

The widespread use of immune checkpoint inhibitors (ICIs) in clinical practice has broadened our understanding of their immune-related adverse events (irAEs). IrAEs, including musculoskeletal adverse events, remain a significant concern. While ICI-associated arthritis is a well-documented musculoskeletal side effect of ICI therapy, the direct effects of ICIs on bone in patients with cancer are poorly understood. There is emerging evidence to support the hypothesis that ICIs adversely impact bone turnover and can lead to osteoporosis and fragility fractures, which are not currently recognized as irAEs.

Deciphering the dynamics of methicillin-resistant Staphylococcus aureus biofilm formation: from molecular signaling to nanotherapeutic advances.

Methicillin-resistant Staphylococcus aureus (MRSA) represents a global threat, necessitating the development of effective solutions to combat this emerging superbug. In response to selective pressures within healthcare, community, and livestock settings, MRSA has evolved increased biofilm formation as a multifaceted virulence and defensive mechanism, enabling the bacterium to thrive in harsh conditions. This review discusses the molecular mechanisms contributing to biofilm formation across its developmental stages, hence representing a step forward in developing promising strategies for impeding or eradicating biofilms. During staphylococcal biofilm development, cell wall-anchored proteins attach bacterial cells to biotic or abiotic surfaces; extracellular polymeric substances build scaffolds for biofilm formation; the cidABC operon controls cell lysis within the biofilm, and proteases facilitate dispersal. Beside the three main sequential stages of biofilm formation (attachment, maturation, and dispersal), this review unveils two unique developmental stages in the biofilm formation process for MRSA; multiplication and exodus. We also highlighted the quorum sensing as a cell-to-cell communication process, allowing distant bacterial cells to adapt to the conditions surrounding the bacterial biofilm. In S. aureus, the quorum sensing process is mediated by autoinducing peptides (AIPs) as signaling molecules, with the accessory gene regulator system playing a pivotal role in orchestrating the production of AIPs and various virulence factors. Several quorum inhibitors showed promising anti-virulence and antibiofilm effects that vary in type and function according to the targeted molecule. Disrupting the biofilm architecture and eradicating sessile bacterial cells are crucial steps to prevent colonization on other surfaces or organs. In this context, nanoparticles emerge as efficient carriers for delivering antimicrobial and antibiofilm agents throughout the biofilm architecture. Although metal-based nanoparticles have been previously used in combatting biofilms, its non-degradability and toxicity within the human body presents a real challenge. Therefore, organic nanoparticles in conjunction with quorum inhibitors have been proposed as a promising strategy against biofilms. As nanotherapeutics continue to gain recognition as an antibiofilm strategy, the development of more antibiofilm nanotherapeutics could offer a promising solution to combat biofilm-mediated resistance.

Human Leukocyte Antigen-G (HLA-G) Expression in Precancerous and Cancerous Cervical Lesions: Association with Human Papilloma Virus Infection and Host Immune Response.

Human leukocyte antigen-G (HLA-G) is a non-classical HLA-class Ib molecule with multiple immunoregulatory properties. Its main functions in physiological conditions are to abolish maternal immune cell activity against fetus and to establish immune tolerance at the maternal-fetal interface. Cervical tumor cells have been reported to express HLA-G which is one of the immunomodulatory molecules that is involved in every phase of cancer immunoediting. It has inhibitory functions against natural killer (NK) cells, T-lymphocytes, and antigen-presenting cells (APCs). The purpose of this study was to investigate the HLA-G expression in precancerous (squamous intraepithelial cervical lesion) and cancer cervix and determine HLA-G expression relation to HPV infection as well as host immune response. The study included 48 paraffin embedded cervical tissue sections [32 squamous intraepithelial lesion (SIL) {16 low grade lesions (LSIL) and 16 high grade lesions (HSIL)} and 16 cervical cancer tissue sections]. All tissue sections were examined for HLA-G expression by real time PCR and for host immune response by estimating the number of tumor infiltrating lymphocyte (TIL) and NK CD57+ cells. HLA-G expression increased progressively from precancerous and cancerous cervical lesions. There was an inverse relationship between HLA-G expression and estimated number of TILs and NK CD57+ cells. No significant statistical difference between HPV positive and HPV negative cervical lesions as regards HLA-G expression was detected. In conclusion, HLA-G is a potential biomarker for the diagnosis and prognosis of cervical cancer as there was a progressive increase in expression of HLA-G in precancerous and cancerous cervical lesion. It is functionally involved in tumor escape mechanisms as observed by inhibition of host immune response and more studies are needed to design strategies for blockade of HLA G expression or elimination of HLA G expressing cancer cells as this may be important to the efficacy of anticancer therapies.