Wayne State University School of Medicine

Vulvovaginal candidiasis is one of the most prevalent infections in women worldwide. Together with its recurrent form, it affects millions of women annually, causing significant symptoms and severely impacting quality of life. This review examines the pathophysiology, risk factors, microbiome interactions, clinical manifestations, and challenges in diagnosing and managing vulvovaginal candidiasis, with emphasis on recurrent vulvovaginal candidiasis. While Candida albicans is the primary cause, non-albicans species are increasingly common. Multiple factors contribute to both forms, including hormonal changes, diabetes, antibiotic use, immune dysfunction, and genetics. The vaginal microbiome plays a key role in maintaining homeostasis and preventing Candida overgrowth. Symptoms such as itching, discharge, and soreness overlap with other conditions, complicating the diagnosis. Standard treatment involves topical or systemic antifungals, but recurrence and resistance are frequent. Emerging strategies include novel antifungals, immunomodulators, and vaccines. Future approaches should focus on modulating host and environmental factors to prevent recurrence, reduce resistance, and improve outcomes.

The tumor bystander effect describes the ability of cells sustaining therapeutic treatment damage to transmit distress signals to neighboring unharmed cells and change their behavior. Photodynamic therapy (PDT), which uses light for activation of photosensitizing drugs in targeted lesions to produce cytotoxic damage, is one of the cancer treatment modalities inducing highly robust bystander effects. This is caused to a large extent by the propensity of PDT for creating extensive lipid peroxidation damage and related instigation of ferroptotic cell death. Lipid peroxides appear to be major participants in intercellular signaling generating the bystander effect and orchestrating ferroptosis that appears to have a pivotal role in propagating the lethal (therapeutically beneficial) form of bystander response. In contrast, nitric oxide (NO) released from PDT-treated cancer cells has emerged as a major signal for therapeutically detrimental bystander effects due to promoting tumor growth and metastasis. It is becoming increasingly evident that exploiting the bystander response can be an attractive strategy for improving tumoricidal depth with consequently elevated tumor cure rates following PDT treatment. A two-pronged approach is proposed for achieving this goal: (i) inactivating iNOS enzyme with a specific pharmacologic inhibitor, and (ii) amplifying the induction of cytotoxic ferroptosis in nearby cells initially unaffected by photodamage, thereby limiting their ability to promote tumor expansion.

Fine particulate matter (PM2.5) is routinely monitored worldwide to support environmental regulation and public health policy. Commonly reported metrics, including annual mean concentrations and short-term regulatory exceedance counts, provide essential summaries of long-term exposure and episodic events but do not fully characterize the distribution of daily pollution levels; exceedance counts also depend on policy-specific thresholds. To jointly characterize the magnitude and frequency of elevated PM2.5 concentrations, we introduce the PM2.5 Magnitude–Rank Index (PMRI), defined as the largest integer k such that at least k days in a year have daily mean PM2.5 concentrations ≥ k µg/m3. For example, a PMRI of 23 indicates that at least 23 days had concentrations of 23 µg/m3 or higher. Applied to 918 qualifying Metropolitan Statistical Area-years (MSA-years) from 96 U.S. metropolitan areas during 2013–2022, PMRI ranged from 6 to 38 (median, 16). It correlated strongly with the annual mean (Spearman ρ = 0.83), annual 98th percentile (ρ = 0.95), and number of days ≥ 15 µg/m3 (ρ = 0.96), while distinguishing MSA-years with similar annual means but different concentration–frequency profiles. By formalizing the magnitude–frequency relationship in an intuitive, threshold-free form, PMRI offers a transparent complement to conventional metrics for characterizing particulate pollution.

The nervous system is increasingly recognized as a dynamic and regulatory component of the tumor microenvironment playing critical roles in cancer initiation, progression, metastasis, and resistance to therapy. Recent evidence in cancer neuroscience have revealed a specialized “neural niche” a microanatomical and functional domain enriched in neural inputs and neuromodulatory signals orchestrated through bidirectional communication between tumor, nervus system and immune cellsCancer cells secrete neurotrophic factors such as nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and glial cell line-derived neurotrophic factor (GDNF) to attract and remodel peripheral innervation. Infiltrating nerve fibers, in turn, release neurotransmitters (e.g., norepinephrine, acetylcholine) and neuropeptides (e.g., substance P, calcitonin gene-related peptide) that influence not only tumor growth, angiogenesis but also immune cell polarization, T cell exhaustion, dendritic cell maturation and myeloid derived suppressor cell recruitment. This neural-immune crosstalk establishes immune suppressive microenvironment that facilitates tumor immune escape and leading to metastatic progression. Perineural invasion (PNI), a distinct pathological process of tumor dissemination, further exemplifies neuroepithelial integration and correlates with recurrence, pain and poor prognosis across multiple solid tumors. Beyond local interactions, chronic stress and systemic neuroendocrine activation via the hypothalamic-pituitary-adrenal (HPA) axis and sympathetic-adrenal-medullary networks, contribute to tumor-promoting immunosuppression through glucocorticoid signaling and sympathetic responses. In this review, we discuss mechanistically integrated and clinical relevant synthesis of tumor-neuron-immune interactions. We emphasize recent conceptual advances, including autonomic balance, systemic neuroendocrine feedback and therapeutic strategies targeting this axis. These insights establish a framework for future translational research and development of neuromodulatory therapies that complement immunotherapy as well as conventional therapeutics.

Fungal infections have become an integral and increasingly complex component of modern intensive care medicine [...]