Modulation of hypoxia-inducible factor-1 signaling pathways in cancer angiogenesis, invasion, and metastasis by natural compounds: a comprehensive and critical review.

Tumor cells employ multiple signaling mediators to escape the hypoxic condition and trigger angiogenesis and metastasis. As a critical orchestrate of tumorigenic conditions, hypoxia-inducible factor-1 (HIF-1) is responsible for stimulating several target genes and dysregulated pathways in tumor invasion and migration. Therefore, targeting HIF-1 pathway and cross-talked mediators seems to be a novel strategy in cancer prevention and treatment. In recent decades, tremendous efforts have been made to develop multi-targeted therapies to modulate several dysregulated pathways in cancer angiogenesis, invasion, and metastasis. In this line, natural compounds have shown a bright future in combating angiogenic and metastatic conditions. Among the natural secondary metabolites, we have evaluated the critical potential of phenolic compounds, terpenes/terpenoids, alkaloids, sulfur compounds, marine- and microbe-derived agents in the attenuation of HIF-1, and interconnected pathways in fighting tumor-associated angiogenesis and invasion. This is the first comprehensive review on natural constituents as potential regulators of HIF-1 and interconnected pathways against cancer angiogenesis and metastasis. This review aims to reshape the previous strategies in cancer prevention and treatment.

Current advances in nanoformulations of therapeutic agents targeting tumor microenvironment to overcome drug resistance.

The tumor microenvironment (TME) plays a pivotal role in cancer development and progression. In this line, revealing the precise mechanisms of the TME and associated signaling pathways of tumor resistance could pave the road for cancer prevention and efficient treatment. The use of nanomedicine could be a step forward in overcoming the barriers in tumor-targeted therapy. Novel delivery systems benefit from enhanced permeability and retention effect, decreasing tumor resistance, reducing tumor hypoxia, and targeting tumor-associated factors, including immune cells, endothelial cells, and fibroblasts. Emerging evidence also indicates the engagement of multiple dysregulated mediators in the TME, such as matrix metalloproteinase, vascular endothelial growth factor, cytokines/chemokines, Wnt/ß-catenin, Notch, Hedgehog, and related inflammatory and apoptotic pathways. Hence, investigating novel multitargeted agents using a novel delivery system could be a promising strategy for regulating TME and drug resistance. In recent years, small molecules from natural sources have shown favorable anticancer responses by targeting TME components. Nanoformulations of natural compounds are promising therapeutic agents in simultaneously targeting multiple dysregulated factors and mediators of TME, reducing tumor resistance mechanisms, overcoming interstitial fluid pressure and pericyte coverage, and involvement of basement membrane. The novel nanoformulations employ a vascular normalization strategy, stromal/matrix normalization, and stress alleviation mechanisms to exert higher efficacy and lower side effects. Accordingly, the nanoformulations of anticancer monoclonal antibodies and conventional chemotherapeutic agents also improved their efficacy and lessened the pharmacokinetic limitations. Additionally, the coadministration of nanoformulations of natural compounds along with conventional chemotherapeutic agents, monoclonal antibodies, and nanomedicine-based radiotherapy exhibits encouraging results. This critical review evaluates the current body of knowledge in targeting TME components by nanoformulation-based delivery systems of natural small molecules, monoclonal antibodies, conventional chemotherapeutic agents, and combination therapies in both preclinical and clinical settings. Current challenges, pitfalls, limitations, and future perspectives are also discussed.

Avocado (Persea americana Mill) and its phytoconstituents: potential for cancer prevention and intervention.

Dietary compounds, including fruits, vegetables, nuts, and spices, have been shown to exhibit anticancer properties due to their high concentrations of vitamins, minerals, fiber, and secondary metabolites, known as phytochemicals. Although emerging studies suggest that avocado (Persea americana Mill) displays antineoplastic properties in addition to numerous other health benefits, current literature lacks an updated comprehensive systematic review dedicated to the anticancer effects of avocado. This review aims to explore the cancer-preventive effects of avocados and the underlying molecular mechanisms. The in vitro studies suggest the various avocado-derived products and phytochemicals induced cytotoxicity, reduced cell viability, and inhibited cell proliferation. The in vivo studies revealed reduction in tumor number, size, and volume as well. The clinical studies demonstrated that avocado leaf extract increased free oxygen radical formation in larynx carcinoma tissue. Various avocado products and phytochemicals from the avocado fruit, including avocatin-B, persin, and PaDef defensin, may serve as viable cancer prevention and treatment options based on current literature. Despite many favorable outcomes, past research has been limited in scope, and more extensive and mechanism-based in vivo and randomized clinical studies should be performed before avocado-derived bioactive phytochemicals can be developed as cancer preventive agents.

Serratia Sacroiliitis Secondary to Intravenous Drug Use: A Case Report.

Serratia spp. are ubiquitous, opportunistic, and infectious organisms that have historically been known to infect the upper respiratory, urinary, and circulatory systems. This manuscript presents the case of a 35-year-old White female with a past medical history of polysubstance abuse, intravenous drug use (IVDU), and poor dentition who was admitted to a community hospital with complaints of lower back pain for 10 days following the recent completion of treatment for a suspected epidural abscess. Per her report, her last IVDU with fentanyl was 11 days prior, and she admitted to using various sources of water to inject her drugs. Magnetic resonance imaging with contrast was significant for possible infectious sacroiliitis, and blood cultures grew Serratia marcescens. Due to this patient's extensive IVDU history, in-patient ceftriaxone was chosen over discharging the patient with a peripherally inserted central catheter line. Serratia spp.bacteremia with concomitant septic sacroiliitis in the setting of IVDU is an extremely rare presentation. Due to the nonspecific presentation of sacroiliitis, multidrug resistance profile of Serratia spp., and high mortality rate associated with S. marcescens sepsis, early detection and diagnosis is paramount in similar patients with extensive risk factors.

Salvage Treatment for a Periprosthetic Humeral Nonunion: A Case Report.

The patient, a 69-year-old female, presented one year after receiving a total elbow arthroplasty with a nonunion periprosthetic fracture of the humerus. Due to the patient's severe osteoarthritis of the ipsilateral shoulder and significant humeral deformity, a procedure linking the total elbow arthroplasty to the reverse shoulder implant via a cemented allograft-composite linkage sleeve was performed. Previous literature suggests upper extremity salvage surgery using large-scale allografts is successful in treating large tumor or infection-derived defects, though data is lacking as to whether this treatment is effective in periprosthetic fractures in patients with significant comorbidities. This patient's success in the postoperative year supports the use of allograft-composite reconstruction followed by linkage to a reverse shoulder implant as a salvage treatment for periprosthetic fractures under certain conditions, such as multiple adjacent implants, bone deformity, and severe osteoarthritis.

Osteopathic manipulative treatment for chronic inflammatory diseases.

Chronic inflammatory diseases (CIDs) are debilitating and potentially lethal illnesses that affect a large proportion of the global population. Osteopathic manipulative treatment (OMT) is a manual therapy technique developed and performed by osteopathic physicians that facilitates the body's innate healing processes. Therefore, OMT may prove a beneficial anti-inflammatory modality useful in the management and treatment of CIDs. This work aims to objectively evaluate the therapeutic benefits of OMT in patients with various CIDs. In this review, a structured literature search was performed. The included studies involving asthma, chronic obstructive pulmonary disease, irritable bowel syndrome, ankylosing spondylitis, and peripheral arterial disease were selected for this work. Various OMT modalities, including lymphatic, still, counterstain, and muscle energy techniques, were utilized. Control treatments included sham techniques, routine care, or no treatment. OMT utilization led to variable patient outcomes in individuals with pathologies linked to CID.

Concussion Reduction in Division I and II Athletes: Effects of Simple Cervical Spine Exercise Regimen.

INTRODUCTION:  Primary preventative medicine lacks a consensus on effective concussion prevention strategies for collegiate athletes. Cervical strength has been identified as a potential factor in concussion risk reduction. This study evaluates the impact of a commercially available, portable cervical muscle stretching and strengthening device, NeckX®, on cervical strength, range of motion (ROM), and concussion incidence in collegiate athletes participating in high-concussion-risk sports. METHODS:  A single-arm prospective cohort study was conducted with 162 collegiate athletes from various sports. Participants underwent a 12-week neck exercise protocol using the NeckX® device. Clinical data, including neck strength and ROM, were collected at weeks 0, 6, and 12. Concussion incidence was self-reported by participants and cross-referenced with records from the athletic department. Data were analyzed for significant neck strength and ROM changes throughout the 12-week study. A two-way analysis of variance multiple comparisons with the Tukey-Kramer significant difference test was utilized, using the Holm-Sidak method, with an alpha of 0.05. RESULTS:  All athletic teams experienced a significant increase in cervical strength during the 12-week intervention (α = 0.05, p < 0.05). Increases in cervical flexion and extension force were most consistent between teams. Cervical ROM increased significantly in male and female soccer players (α = 0.05, p < 0.05). The overall incidence of head and neck injuries, including concussions, was reduced to 6.60% during the study period, the lowest recorded value in the university's athletic department history. CONCLUSION:  The use of the NeckX® device for 12 weeks was effective in enhancing pericervical muscle strength and ROM while reducing concussion incidence in collegiate athletes participating in high-concussion-risk sports. Interestingly, the positive outcomes were consistent for both males and females, indicating the universal advantages of neck training among collegiate athletes. These findings support existing research on the benefits of cervical strengthening exercises for reducing concussions in collegiate athletes and highlight the convenience and affordability of using this device.

Withaferin A: A Pleiotropic Anticancer Agent from the Indian Medicinal Plant Withania somnifera (L.) Dunal.

Cancer represents the second most deadly disease and one of the most important public health concerns worldwide. Surgery, chemotherapy, radiation therapy, and immune therapy are the major types of treatment strategies that have been implemented in cancer treatment. Unfortunately, these treatment options suffer from major limitations, such as drug-resistance and adverse effects, which may eventually result in disease recurrence. Many phytochemicals have been investigated for their antitumor efficacy in preclinical models and clinical studies to discover newer therapeutic agents with fewer adverse effects. Withaferin A, a natural bioactive molecule isolated from the Indian medicinal plant Withania somnifera (L.) Dunal, has been reported to impart anticancer activities against various cancer cell lines and preclinical cancer models by modulating the expression and activity of different oncogenic proteins. In this article, we have comprehensively discussed the biosynthesis of withaferin A as well as its antineoplastic activities and mode-of-action in in vitro and in vivo settings. We have also reviewed the effect of withaferin A on the expression of miRNAs, its combinational effect with other cytotoxic agents, withaferin A-based formulations, safety and toxicity profiles, and its clinical potential.