PIKfyve controls dendritic cell function and tumor immunity.

The modern armamentarium for cancer treatment includes immunotherapy and targeted therapy, such as protein kinase inhibitors. However, the mechanisms that allow cancer-targeting drugs to effectively mobilize dendritic cells (DCs) and affect immunotherapy are poorly understood. Here, we report that among shared gene targets of clinically relevant protein kinase inhibitors, high PIKFYVE expression was least predictive of complete response in patients who received immune checkpoint blockade (ICB). In immune cells, high PIKFYVE expression in DCs was associated with worse response to ICB. Genetic and pharmacological studies demonstrated that PIKfyve ablation enhanced DC function via selectively altering the alternate/non-canonical NF-κB pathway. Both loss of Pikfyve in DCs and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively controls DCs, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.

Targeting the lipid kinase PIKfyve upregulates surface expression of MHC class I to augment cancer immunotherapy.

Despite the remarkable clinical success of immunotherapies in a subset of cancer patients, many fail to respond to treatment and exhibit resistance. Here, we found that genetic or pharmacologic inhibition of the lipid kinase PIKfyve, a regulator of autophagic flux and lysosomal biogenesis, upregulated surface expression of major histocompatibility complex class I (MHC-I) in cancer cells via impairing autophagic flux, resulting in enhanced cancer cell killing mediated by CD8+ T cells. Genetic depletion or pharmacologic inhibition of PIKfyve elevated tumor-specific MHC-I surface expression, increased intratumoral functional CD8+ T cells, and slowed tumor progression in multiple syngeneic mouse models. Importantly, enhanced antitumor responses by Pikfyve-depletion were CD8+ T cell- and MHC-I-dependent, as CD8+ T cell depletion or B2m knockout rescued tumor growth. Furthermore, PIKfyve inhibition improved response to immune checkpoint blockade (ICB), adoptive cell therapy, and a therapeutic vaccine. High expression of PIKFYVE was also predictive of poor response to ICB and prognostic of poor survival in ICB-treated cohorts. Collectively, our findings show that targeting PIKfyve enhances immunotherapies by elevating surface expression of MHC-I in cancer cells, and PIKfyve inhibitors have potential as agents to increase immunotherapy response in cancer patients.

A Rare Case of Localized Hypertrichosis in Conjunction with Erythema Nodosum.

Acquired hypertrichosis can occur in local inflammation. Erythema nodosum (EN) is a hypersensitivity reaction to various underlying antigenic stimuli including Mycobacterium tuberculosis, which causes inflammation in the septa of subcutaneous fat. There were several case reports that describe the association of localized hypertrichosis (LH) with traumatic panniculitis and lupus panniculitis. To our knowledge, this is the first reported case of acquired LH associated with EN. Thus, EN can be added to the list of causes of localized hypertrichosis.

Clinical characteristics of chronic rhinitis following stroke.

Background: We previously observed that patients with stroke complained of rhinitis symptoms that developed following the occurrence of stroke. Objectives: To investigate the relationship between chronic rhinitis (CR) and stroke. Methods: This retrospective study analyzed the medical records and questionnaires of patients with stroke who visited our outpatient clinic from June to December 2020. Stroke lesions were mainly classified as supratentorial, infratentorial, and supra/infratentorial lesions. Supratentorial lesions were further divided into cortex, subcortex, and mixed. Participants were screened for CR and were subsequently divided into the CR and non-CR groups. The Sino-Nasal Outcome Test questionnaire and a questionnaire on autonomic nervous system symptoms were administered to all patients. Results: Clinically evaluated indicators were not significantly different between the two groups. The number of patients with lesions in both the cortex and subcortex was significantly higher in the CR group than in the non-CR group. The risk of CR was higher in male patients with stroke than their female counterparts; additionally, the risk of CR was higher in patients with stroke who had both cortical and subcortical lesions, as well as autonomic dysfunction. Conclusions: Individuals with subcortical stroke damage had a greater probability of developing CR. The risk was increased in men, as compared with that in women, when autonomic symptoms were present.

Intersection of immune and oncometabolic pathways drives cancer hyperprogression during immunotherapy.

Immune checkpoint blockade (ICB) can produce durable responses against cancer. We and others have found that a subset of patients experiences paradoxical rapid cancer progression during immunotherapy. It is poorly understood how tumors can accelerate their progression during ICB. In some preclinical models, ICB causes hyperprogressive disease (HPD). While immune exclusion drives resistance to ICB, counterintuitively, patients with HPD and complete response (CR) following ICB manifest comparable levels of tumor-infiltrating CD8+ T cells and interferon γ (IFNγ) gene signature. Interestingly, patients with HPD but not CR exhibit elevated tumoral fibroblast growth factor 2 (FGF2) and ß-catenin signaling. In animal models, T cell-derived IFNγ promotes tumor FGF2 signaling, thereby suppressing PKM2 activity and decreasing NAD+, resulting in reduction of SIRT1-mediated ß-catenin deacetylation and enhanced ß-catenin acetylation, consequently reprograming tumor stemness. Targeting the IFNγ-PKM2-ß-catenin axis prevents HPD in preclinical models. Thus, the crosstalk of core immunogenic, metabolic, and oncogenic pathways via the IFNγ-PKM2-ß-catenin cascade underlies ICB-associated HPD.

Distribution Analysis of Candida albicans according to Sex and Age in Clinical Specimen Testing for Sexually Transmitted Diseases.

The prevalence of candidiasis, a contagious disease with high morbidity and mortality, has sharply increased globally over the last two decades. Candida albicans can cause serious infections in patients with weak immunity and in recipients of prolonged antibiotic treatment. Consequently, rapid and accurate identification of species can play an important role in the treatment of candidiasis. Here, we investigated the positive rate and infection trend of Candida albicans according to age, specimen type, and sex using multiplex real-time polymerase chain reactionbased testing of samples collected for the diagnosis of sexually transmitted diseases in Korea between 2018 and 2020. When the type of specimen collected was a swab, the positive rate of Candida albicans was higher among younger women, and tended to decrease with age. Analysis of swab samples revealed higher positive rates than urinalysis. The reduction trend in positive rates by age was comparable between the overall samples and urine specimens. Among male patients, the positive rate did not differ substantially across the various types of specimens collected. Previous studies have shown a higher prevalence of non-albicans Candida species than Candida albicans in clinical specimens, and exclusion of the former from our analysis may be a limitation of this study. However, our findings contribute significantly to the literature because globally, there is a paucity of epidemiological studies using molecular techniques to detect Candida albicans in sexually transmitted disease test samples.

Reliability of electroencephalogram indicator and event related potential in subacute stroke.

Cognitive impairment is observed in 12% to 56% of stroke patients, and screening for cognitive impairment is often complex and time-consuming, with results dependent on patient compliance. Therefore, there is a need for an objective method to assess cognitive impairment regardless of patient compliance. Objective evaluation methods include electroencephalogram (EEG) and event-related potential (ERP). This study was conducted to assess intra-tester reliability of resting EEG-based spectral features and auditory/visual P300 latency/amplitude in patients with subacute ischemic stroke. Twenty patients with subacute ischemic stroke were included in the study. The resting EEG and P300 wave using an auditory and visual oddball paradigm were measured at baseline and once again in 24 hours. The following electrode positions (10-20 system) were constantly recorded: F3 (Frontal), Fz, F4, C3 (Central), Cz, C4, P3 (Parietal), Pz, P4. DAR (delta/alpha ratio) and BSI (brain symmetry index) were determined using EEG data. F3 and F4, C3 and C4 and P3 and P4 were switched according to the stroke side and classified as affected hemisphere (AH) and unaffected hemisphere (UH) after the evaluation. In ERP, the amplitude and latency of P300 were obtained. In reliability analysis of EEG-based spectral characteristics, significant reliability was observed for DAR (ICC = 0.447), BSldir (ICC = 0.713) and BSIdirtheta (ICC = 0.724) (Table 4). DAR was showed a poor ICC level, and BSIdir and BSIdirtheta had a moderate ICC level. Visual P300 latency showed excellent intraclass correlation coefficient (ICC) in several montages (PUH = 0.972, Pz = 0.945). In 6 montages, auditory P300 latency was reliable, while in 9 montages, visual P300 latency was reliable. In 4 montages, auditory P300 amplitude was reliable, while visual P300 amplitude was reliable in 7. The visual P300 was more reliable than the auditory P300. The ICC values for P300 latency were greater than those for amplitude. Therefore, when ERP is performed on subacute stroke patients, visual has higher reliability than auditory.

The Low-Fluence Q-Switched Nd:YAG Laser Treatment for Melasma: A Systematic Review.

Melasma is a common pigmentary disorder with a complex pathogenesis, of which the treatment is challenging. Conventional treatment often leads to inconsistent results with unexpected pigmentary side effects and high recurrence rates. Recently, the low-fluence Q-switched Nd:YAG laser (LFQSNY) has been widely used for treating melasma, especially in Asia. We reviewed literatures on the LFQSNY treatment of melasma published between 2009 and May 2022 to evaluate the efficacy and adverse events, including its combination therapy. A systematic PubMed search was conducted and a total of 42 articles were included in this study. It was hard to summarize the heterogenous studies, but LFQSNY appeared to be a generally effective and safe treatment for melasma considering the results of previous conventional therapies. However, mottled hypopigmentation has been occasionally reported to develop and persist as an adverse event of LFQSNY, which may be associated with the high accumulated laser energy. When used aggressively, even LFQSNY can induce hyperpigmentation via unwanted inflammation, especially in darker skin. Although few studies have reported considerable recurrence rates three months after treatment, unfortunately, there is a lack of the long-term follow-up results of LFQSNY in melasma. To enhance the effectiveness and reduce the adverse events, LFQSNY has been used in combination with other treatment modalities in melasma, including topical bleaching agents, oral tranexamic acid, chemical peeling, or diverse energy-based devices, which generally reduced side effects with or without significant superior efficacy compared to LFQSNY alone.

Viral Status Predicts the Patterns of Genome Methylation and Decitabine Response in Merkel Cell Carcinoma.

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma that is classified as Merkel cell polyomavirus-positive (virus positive [VP]) or Merkel cell polyomavirus-negative (virus negative [VN]). Epigenetic changes, such as DNA methylation, can alter gene expression and influence cancer progression. However, patterns of DNA methylation and the therapeutic efficacy of hypomethylating agents have not been fully explored in MCC. We characterized genome-wide DNA methylation in 16 MCC cell lines from both molecular subclasses in comparison with other cancer types and found that the overall profile of MCC is similar to that of small-cell lung carcinoma. Comparison of VP MCC with VN MCC revealed 2,260 differentially methylated positions. The hypomethylating agent decitabine upregulated the expression of antigen-presenting machinery in MCC cell lines and stimulated membrane expression of HLA-A in VP and VN MCC xenograft tumors. Decitabine also induced prominent caspase- and large T antigen‒independent cell death in VP MCC, whereas VN MCC cell lines displayed decreased proliferation without increased cell death. In mouse xenografts, decitabine significantly decreased the size of VP tumors but not that of VN tumors. Our findings indicate that viral status predicts genomic methylation patterns in MCC and that decitabine may be therapeutically effective against MCC through antiproliferative effects, cell death, and increased immune recognition.

Augmented reality in anesthesia, pain medicine and critical care: a narrative review.

Augmented reality (AR) is the integration of computer-generated information with the user's environment in real time. AR is used in many industries, including healthcare, where it has gained significant popularity. Recent strides in hardware and software engineering have reduced the cost of AR, while significantly improving the experience for users and developers. One of the first applications of AR technology in perioperative medicine has been in the identification of anatomical structures for regional blocks and peripheral or central vascular access. AR has also been implemented in pediatric care to reduce periprocedural anxiety. In this narrative review, we summarize the current role of AR in anesthesiology, pain medicine, and critical care.

Relation of Flatfoot Severity with Flexibility and Isometric Strength of the Foot and Trunk Extensors in Children.

BACKGROUND: Flatfoot is a deformity in which the foot is flattened due to a decrease in or loss of the medial longitudinal arch. STATEMENT OF THE PROBLEM: Few studies have investigated the relationship between the severity of flat feet, trunk strength, and joint flexibility. PURPOSE: The aim of this study is to investigate the relationship between the severity of flatfoot and joint flexibility and foot and trunk strength in children with flexible flatfoot. METHODS: This study included 16 children (boys, 12; girls, 4; age, 4~8 years) with flexible flatfeet. We examined the resting calcaneal stance position angle (RCSPA) and foot posture index (FPI) scores for clinical severity and radiographic parameters, such as calcaneal pitch angle, talometatarsal angle (TMA), and talocalcaneal angle (TCA). Muscle thicknesses of the tibialis posterior (TP), peroneus longus (PL), and L1 multifidus were measured by sonography. Isometric contraction of ankle inversion, eversion in a seating position, and lumbar extension at a prone position were induced using a handheld dynamometer to measure the maximum muscle strength for each muscle. Beighton's scoring system was used to assess joint flexibility by evaluating the hyperextension of the joint for each category when performing stretching motion. Spearman's rank correlation coefficient for nonparametric data was used. RESULTS: The FPI showed a moderately negative correlation with the muscle thickness of TP (r = -0.558, p = 0.009) and L1 multifidus (r = -0.527, p = 0.012), and the strength of the ankle inverter (r = -0.580 p = 0.005) and lumbar extensor (r = -0.436 p = 0.043). RCSPA showed a moderately positive correlation with TCA (r = 0.510, p = 0.006). Beighton's score showed no significant correlation with all parameters. CONCLUSION: In children with flatfoot, FPI reflected the clinical severity; thus, the more severe the symptoms, the weaker the ankle inverter and lumbar extensor.

Autophagy Inhibition by Targeting PIKfyve Potentiates Response to Immune Checkpoint Blockade in Prostate Cancer.

Multi-tyrosine kinase inhibitors (MTKIs) have thus far had limited success in the treatment of castration-resistant prostate cancer (CRPC). Here, we report a phase I-cleared orally bioavailable MTKI, ESK981, with a novel autophagy inhibitory property that decreased tumor growth in diverse preclinical models of CRPC. The anti-tumor activity of ESK981 was maximized in immunocompetent tumor environments where it upregulated CXCL10 expression through the interferon gamma pathway and promoted functional T cell infiltration, which resulted in enhanced therapeutic response to immune checkpoint blockade. Mechanistically, we identify the lipid kinase PIKfyve as the direct target of ESK981. PIKfyve-knockdown recapitulated ESK981's anti-tumor activity and enhanced the therapeutic benefit of immune checkpoint blockade. Our study reveals that targeting PIKfyve via ESK981 turns tumors from cold into hot through inhibition of autophagy, which may prime the tumor immune microenvironment in advanced prostate cancer patients and be an effective treatment strategy alone or in combination with immunotherapies.

Hormesis effects of gamma radiation on growth of quinoa (Chenopodium quinoa).

PURPOSE: Quinoa is an annual plant that grows well in high altitude regions with high radiation and ultraviolet intensity. It has known that high-dose radiation damages living organisms, but low-dose radiation also has a beneficial effect. Therefore, the purpose of this study is to investigate the hormesis effect of gamma-ray on quinoa by growth analysis and hyperspectral imaging. MATERIALS AND METHODS: Quinoa seeds were irradiated at 50, 100, and 200 Gy emitted by 60CO. Subsequently, the seeds were germinated and transplanted into pots, then conducted growth analysis and physiological evaluation every week, and hyperspectral imaging. Photosynthetic ability was measured at 35 days after transplanting (DAT), and the plants for each dose were divided into aerial and underground parts for biomass evaluation at 91 DAT. Various vegetation indices were estimated from 14 to 35 DAT by hyperspectral analysis, and the specific bands were extracted based on the PLS model using plant height, SPAD value, and chlorophyll fluorescence parameters. RESULTS: We found that plant height and biomass were increased in quinoa plants treated with a low dose (50 Gy) as compared to control. Chlorophyll content and chlorophyll fluorescence were not different between doses at the early growth stage, but as growth progressed, the plant irradiated at 200 Gy began to be lower. The photosynthetic ability of the quinoa plant treated at 50 Gy was greater than other plants at 35 DAT. The vegetation indices related to the pigment status also were higher in the plants treated by irradiation at 50 Gy than the plants grown in other doses treatment units at the beginning of the growth. Using the PLS model we collected sensitive band wavelengths from hyperspectral image analysis. Among the collected bands, eight bands closely related to plant height, nine bands to chlorophyll content, and ten bands to chlorophyll fluorescence were identified. CONCLUSION: Our results showed that the growth and physiological parameters of quinoa treated by low dose gamma irradiation to seeds were greater than that of control as well as the plant with higher doses. These findings confirm that the positive changes in the characteristics of quinoa with low dose radiation indicated that hormesis occurs at 50 Gy radiation.