Advances in the targeted theragnostics of osteomyelitis caused by Staphylococcus aureus.

Bone infections caused by Staphylococcus aureus may lead to an inflammatory condition called osteomyelitis, which results in progressive bone loss. Biofilm formation, intracellular survival, and the ability of S. aureus to evade the immune response result in recurrent and persistent infections that present significant challenges in treating osteomyelitis. Moreover, people with diabetes are prone to osteomyelitis due to their compromised immune system, and in life-threatening cases, this may lead to amputation of the affected limbs. In most cases, bone infections are localized; thus, early detection and targeted therapy may prove fruitful in treating S. aureus-related bone infections and preventing the spread of the infection. Specific S. aureus components or overexpressed tissue biomarkers in bone infections could be targeted to deliver active therapeutics, thereby reducing drug dosage and systemic toxicity. Compounds like peptides and antibodies can specifically bind to S. aureus or overexpressed disease markers and combining these with therapeutics or imaging agents can facilitate targeted delivery to the site of infection. The effectiveness of photodynamic therapy and hyperthermia therapy can be increased by the addition of targeting molecules to these therapies enabling site-specific therapy delivery. Strategies like host-directed therapy focus on modulating the host immune mechanisms or signaling pathways utilized by S. aureus for therapeutic efficacy. Targeted therapeutic strategies in conjunction with standard surgical care could be potential treatment strategies for S. aureus-associated osteomyelitis to overcome antibiotic resistance and disease recurrence. This review paper presents information about the targeting strategies and agents for the therapy and diagnostic imaging of S. aureus bone infections.

Use of Surgical Adjuvants Does Not Decrease Recurrence of Aneurysmal Bone Cysts in Surgical Intervention With Pediatric Patients.

BACKGROUND: Aneurysmal bone cysts (ABCs) are benign active tumors often requiring intralesional curettage with or without adjuvants. The primary aim of this study was to analyze whether recurrence is influenced by the use of surgical adjuvants in pediatric patients with ABCs. Secondary aims examined recurrence rates based on age, sex, and physeal contact. METHODS: A retrospective review was performed at a tertiary pediatric hospital from 2004 to 2020. Inclusion criteria consisted of patients treated surgically for histologically confirmed ABCs with a minimum of 6 months follow-up. Patients with treatment for a recurrent tumor or incomplete records were excluded. Patient demographics, location of the lesion, treatment technique, and incidence of recurrence were collected. Statistical analyses were performed using STATA. RESULTS: There were 129 patients (74 males and 55 females) with a mean age of 11.5 ± 4.1 years and an average follow-up of 29.0 ± 25.4 months. The most common locations for ABCs were the femur and tibia. Of the patients, 53.5% had tumors abutting the physis, 28.7% had no physeal contact, and 17.8% had insufficient imaging to evaluate physeal contact. Surgical adjuvants (high-speed burr, coagulation, liquid nitrogen, and/or hydrogen peroxide) were used in 91 of the 129 cases (70.5%). There was no significant difference in recurrence when comparing those who received an adjuvant and those who did not (25.3% vs 23.7%, P = 1.000). Physeal contact was also not significantly associated with recurrence ( P = 0.146). Finally, patients younger than 6 years old were significantly more likely to have recurrence compared with those 6 years old or older (66.7% vs 21.7%, P = 0.007). CONCLUSION: Our study found no association between the use of surgical adjuvants and the risk of recurrence after intralesional curettage for ABCs. Although our study did demonstrate that patients 6 years old or younger had an increased rate of recurrence, no significant association was found regarding physeal contact or sex. These data indicate that surgical adjuvant may not affect the recurrence rates of pediatric patients with ABCs. LEVEL OF EVIDENCE: Level III. This retrospective review compares rates of recurrence based on the choice of surgical adjuvant.

Targeting LIPA independent of its lipase activity is a therapeutic strategy in solid tumors via induction of endoplasmic reticulum stress.

Triple-negative breast cancer (TNBC) has a poor clinical outcome, due to a lack of actionable therapeutic targets. Herein we define lysosomal acid lipase A (LIPA) as a viable molecular target in TNBC and identify a stereospecific small molecule (ERX-41) that binds LIPA. ERX-41 induces endoplasmic reticulum (ER) stress resulting in cell death, and this effect is on target as evidenced by specific LIPA mutations providing resistance. Importantly, we demonstrate that ERX-41 activity is independent of LIPA lipase function but dependent on its ER localization. Mechanistically, ERX-41 binding of LIPA decreases expression of multiple ER-resident proteins involved in protein folding. This targeted vulnerability has a large therapeutic window, with no adverse effects either on normal mammary epithelial cells or in mice. Our study implicates a targeted strategy for solid tumors, including breast, brain, pancreatic and ovarian, whereby small, orally bioavailable molecules targeting LIPA block protein folding, induce ER stress and result in tumor cell death.

Overcoming oncogene addiction in breast and prostate cancers: a comparative mechanistic overview.

Prostate cancer (PCa) and breast cancer (BCa) are both hormone-dependent cancers that require the androgen receptor (AR) and estrogen receptor (ER, ESR1) for growth and proliferation, respectively. Endocrine therapies that target these nuclear receptors (NRs) provide significant clinical benefit for metastatic patients. However, these therapeutic strategies are seldom curative and therapy resistance is prevalent. Because the vast majority of therapy-resistant PCa and BCa remain dependent on the augmented activity of their primary NR driver, common mechanisms of resistance involve enhanced NR signaling through overexpression, mutation, or alternative splicing of the receptor, coregulator alterations, and increased intracrine hormonal synthesis. In addition, a significant subset of endocrine therapy-resistant tumors become independent of their primary NR and switch to alternative NR or transcriptional drivers. While these hormone-dependent cancers generally employ similar mechanisms of endocrine therapy resistance, distinct differences between the two tumor types have been observed. In this review, we compare and contrast the most frequent mechanisms of antiandrogen and antiestrogen resistance, and provide potential therapeutic strategies for targeting both advanced PCa and BCa.

Architectural Modification of Conformal PEG-Bottlebrush Coatings Minimizes Anti-PEG Antigenicity While Preserving Stealth Properties.

Poly(ethylene glycol) (PEG), a linear polymer known for its "stealth" properties, is commonly used to passivate the surface of biomedical implants and devices, and it is conjugated to biologic drugs to improve their pharmacokinetics. However, its antigenicity is a growing concern. Here, the antigenicity of PEG is investigated when assembled in a poly(oligoethylene glycol) methacrylate (POEGMA) "bottlebrush" configuration on a planar surface. Using ethylene glycol (EG) repeat lengths of the POEGMA sidechains as a tunable parameter for optimization, POEGMA brushes with sidechain lengths of two and three EG repeats are identified as the optimal polymer architecture to minimize binding of anti-PEG antibodies (APAs), while retaining resistance to nonspecific binding by bovine serum albumin and cultured cells. Binding of backbone- versus endgroup-selective APAs to POEGMA brushes is further investigated, and finally the antigenicity of POEGMA coatings is assessed against APA-positive clinical plasma samples. These results are applied toward fabricating immunoassays on POEGMA surfaces with minimal reactivity toward APAs while retaining a low limit-of-detection for the analyte. Taken together, these results offer useful design concepts to reduce the antigenicity of polymer brush-based surface coatings used in applications involving human or animal matrices.