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.

CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy.

Cancer immunotherapy restores or enhances the effector function of CD8+ T cells in the tumour microenvironment1,2. CD8+ T cells activated by cancer immunotherapy clear tumours mainly by inducing cell death through perforin-granzyme and Fas-Fas ligand pathways3,4. Ferroptosis is a form of cell death that differs from apoptosis and results from iron-dependent accumulation of lipid peroxide5,6. Although it has been investigated in vitro7,8, there is emerging evidence that ferroptosis might be implicated in a variety of pathological scenarios9,10. It is unclear whether, and how, ferroptosis is involved in T cell immunity and cancer immunotherapy. Here we show that immunotherapy-activated CD8+ T cells enhance ferroptosis-specific lipid peroxidation in tumour cells, and that increased ferroptosis contributes to the anti-tumour efficacy of immunotherapy. Mechanistically, interferon gamma (IFNγ) released from CD8+ T cells downregulates the expression of SLC3A2 and SLC7A11, two subunits of the glutamate-cystine antiporter system xc-, impairs the uptake of cystine by tumour cells, and as a consequence, promotes tumour cell lipid peroxidation and ferroptosis. In mouse models, depletion of cystine or cysteine by cyst(e)inase (an engineered enzyme that degrades both cystine and cysteine) in combination with checkpoint blockade synergistically enhanced T cell-mediated anti-tumour immunity and induced ferroptosis in tumour cells. Expression of system xc- was negatively associated, in cancer patients, with CD8+ T cell signature, IFNγ expression, and patient outcome. Analyses of human transcriptomes before and during nivolumab therapy revealed that clinical benefits correlate with reduced expression of SLC3A2 and increased IFNγ and CD8. Thus, T cell-promoted tumour ferroptosis is an anti-tumour mechanism, and targeting this pathway in combination with checkpoint blockade is a potential therapeutic approach.

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.

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.

Erythema induratum of Bazin in a 10-year-old boy.

Erythema induratum of Bazin (EIB) is a form of tuberculid resulting from hypersensitivity to tuberculosis antigen. EIB occurs most commonly in middle-aged women and is not typically seen in children. Here, we present a rare case of EIB, presenting as a chronic nodular panniculitis, in a 10-year-old Korean boy.

Lipocalin 2: A New Antimicrobial in Mast Cells.

Mast cells (MCs) play a significant role in the innate immune defense against bacterial infection through the release of cytokines and antimicrobial peptides. However, their antimicrobial function is still only partially described. We therefore hypothesized that MCs express additional antimicrobial peptides. In this study, we used FANTOM 5 transcriptome data to identify for the first time that MCs express lipocalin 2 (LCN2), a known inhibitor of bacterial growth. Using MCs derived from mice which were deficient in LCN2, we showed that this antimicrobial peptide is an important component of the MCs' antimicrobial activity against Escherichia coli (E. coli). Since sphingosine-1-phosphate receptors (S1PRs) on MCs are known to regulate their function during infections, we hypothesized that S1P could activate LCN2 production in MCs. Using an in vitro assay, we demonstrated that S1P enhances MCs antimicrobial peptide production and increases the capacity of MCs to directly kill S. aureus and E. coli via an LCN2 release. In conclusion, we showed that LCN2 is expressed by MCs and plays a role in their capacity to inhibit bacterial growth.

Skin commensal bacteria Staphylococcus epidermidis promote survival of melanocytes bearing UVB-induced DNA damage, while bacteria Propionibacterium acnes inhibit survival of melanocytes by increasing apoptosis.

BACKGROUND/PURPOSE: Skin commensal bacteria have been described to help orchestrate skin homeostasis, signaling through innate immunity pathways. This study for the first time aimed at studying the relationship between skin commensals and melanocytes after UVB exposure. METHODS: An in vitro UVB radiation model with normal human epidermal melanocytes (NHMs) and skin commensal bacteria supernatant from Staphylococcus epidermidis and Propionibacterium acnes was established. Melanocytes DNA damage, cyclobutane pyrimidine dimers (CPD), and cellular proliferation marker Ki-67 were measured by ELISA and immunofluorescence staining. Cell apoptosis was assessed by flow cytometry and PCR array and RT-qPCR. RESULTS: Normal human epidermal melanocytes are able to survive and proliferate while bearing DNA damage after UVB radiation. Skin commensal bacteria S. epidermidis and its by-product LTA promote melanocytes survival by inducing upregulation of TRAF1, CASP14, CASP5, and TP73. On the other hand, P. acnes can inhibit UVB-irradiated melanocytes survival by increasing apoptosis. CONCLUSION: Our studies show different aspects of commensal activity on melanocytes during irradiation. The possible balance achieved by the different skin commensal can influence NHM potential to become cancer cells.

Retreatment using a dual mode of low-fluence Q-switched and long-pulse Nd:YAG laser in patients with melasma aggravation after previous therapy.

BACKGROUND: Aggravated melasma after treatment is vulnerable to stimulation, can easily deteriorate, and may be distressing without proper management. OBJECTIVE: To retrospectively assess the effectiveness and safety of combination therapy using low-fluence Q-switched neodymium-doped yttrium aluminum garnet (Nd:YAG) laser (QSNY) and long-pulse Nd:YAG laser (LPNY) (dual toning) in patients with rebound melasma. MATERIALS AND METHODS: A total of 30 patients with aggravated melasma after previous therapy who were treated with dual toning were enrolled. A total of 10 sessions were conducted at 1-week intervals, followed by maintenance treatment. The results were evaluated using the modified Melasma Area and Severity Index (mMASI) and the physician's global assessment (PGA) before and 2 months after completing the 10 treatment sessions. RESULTS: The baseline mMASI was 10.48 ± 3.64, which significantly decreased to 3.22 ± 1.45 2 months after completing the 10 treatment sessions (p < 0.001). Twenty-four patients (80%) had PGA grade 4 (76-100% improvement) and 6 patients (20%) had PGA grade 3 (51-75% improvement). CONCLUSION: Dual toning may be a safe and effective salvage treatment for patients with aggravated melasma after previous treatment. LPNY may stabilize melasma activity to prevent rebound hyperpigmentation via dermal remodeling.

Retrospective analysis of melasma treatment using a dual mode of low-fluence Q-switched and long-pulse Nd:YAG laser vs. low-fluence Q-switched Nd:YAG laser monotherapy.

BACKGROUND: Despite the effectiveness of low-fluence Q-switched Nd:YAG laser (QSNY) treatment in melasma, adverse events, including mottled hypopigmentation (MH) and rebound hyperpigmentation (RH) have been reported. OBJECTIVE: To compare the effectiveness and safety of combination therapy using low-fluence QSNY and long-pulse Nd:YAG laser (LPNY) (Dual toning), with low-fluence QSNY monotherapy (QS toning), in Asian melasma patients. MATERIALS AND METHODS: Patients were treated for 10 sessions at 1-week intervals with QSNY (6 mm spot); 2.5-3.0 J/cm(2) for QS toning (n = 177) or 2.1-2.5 J/cm(2) for dual toning (n = 183). The dual toning group was immediately treated with LPNY (7 mm spot, 15-17 J/cm(2)). The results were evaluated using the modified Melasma Area and Severity Index (mMASI) score and the physician's global assessment. RESULTS: MH or RH were significantly lower (1.1% vs. 14.1%) and the treatment efficacy was improved (median decrease of mMASI, 3.6 vs. 3.0) in the dual toning group compared with the QS toning group. Periorbital melasma showed distinctively high rates of adverse events in the QS toning group (23.9% vs. 5.7%), which were significantly reduced in the dual toning group (2.9%). CONCLUSION: Dual toning could represent a safe and effective treatment for Asian melasma patients, as it is associated with minimal adverse events and improved treatment efficacy compared with QS toning monotherapy.

Egr-1 is a key regulator of IL-17A-induced psoriasin upregulation in psoriasis.

The early growth response (Egr)-1 is a transcriptional factor which plays an important role in the regulation of cell growth, differentiation, cell survival and immune responses. Emerging evidences including our data demonstrate that the Egr-1 expression is up-regulated in the psoriatic skin lesions. The purpose of this study was to investigate the significance and regulatory mechanism of Egr-1 in the pathogenesis of psoriasis. Through microarray analysis, we found out that psoriasin (S100A7) expression was increased in the Egr-1 overexpressed cells. Our results showed that IL-17A increased Egr-1 expression in the skin of psoriatic patients and cultured human keratinocytes. We then investigated activation of mitogen-activated protein kinase as an upstream signal regulator of Egr-1 expression. IL-17A-induced Egr-1 expression was suppressed by ERK inhibitor. In addition, IL-17A induced psoriasin expression in cultured keratinocytes and the skin of IL-17A intradermally injected mouse. IL-17A-mediated psoriasin upregulation was reduced after treatment of small interfering RNAs against Egr-1. Furthermore, the results of chromatin immunoprecipitation assays demonstrated that Egr-1 directly binds the psoriasin promoter. Our findings present a novel signalling mechanism by which IL-17A can induce the Egr-1-dependent psoriasin expression via the ERK pathway in human keratinocytes. This study suggests that Egr-1 may be a novel and important modulator in IL-17A-mediated immune response in psoriasis.

3D reconstruction of skin pathological tissue: the understanding of microrelief pattern and dermal ridge.

AIM: Most studies about the structures of the human skin have been on the general histologic features of the skin. The purpose of this study was to understand the relationship between the microrelief (MR) pattern and histologic structure of the human skin, and to find the usefulness of the three-dimensional reconstruction (3DR) technique of pathological skin tissue. MATERIALS, SUBJECTS, AND METHODS: Human skin specimens were obtained from the medial forearm, abdomen, and volar aspects of the finger tips of cadavers. Two-dimensional surface-viewed images of the skin showing MR patterns were obtained using dry dermoscopy. Histologic structures of the skin were evaluated by 3D images obtained using the 3DR technique. RESULTS: MR was deeper and wider in the abdomen than in the medial side of the forearm. In the medial side of the forearm, 10.27 rete ridges were distributed in a plateau, on average. In the abdomen, about 14.37 rete ridges were distributed in a plateau. From 3DR technique, MR pattern thought to be a superordinate concept to rete ridges. CONCLUSION: The 3DR technique was useful and may allow a better understanding of the pathogenetic changes in the skin surface in aging skin.

A comparison of the scar prevention effect between carbon dioxide fractional laser and pulsed dye laser in surgical scars.

BACKGROUND: The use of ablative lasers based on the fractional approach is a novel strategy for the treatment of postoperative and acne scars in addition to wrinkles. OBJECTIVE: To evaluate and compare the efficacy of carbon dioxide ablative fractional laser (AFL) and the pulsed dye laser (PDL) for the improvement of surgical scars. MATERIALS AND METHODS: Fourteen Korean patients with surgical scars were enrolled for this study. Half of each scar was treated with a 10,600-nm AFL and the contralateral half with the 595-nm PDL. For early intervention of the postoperative scar, the laser treatments were begun after 2 weeks from the Mohs micrographic surgery. RESULTS: Both PDL and AFL produced statistically significant improvements. However, comparatively, there was no statistical difference between them. In each variable, AFL was more effective than PDL in the improvement of pliability and thickness. In contrast, PDL was superior to AFL in the improvement of vascularity and pigmentation. CONCLUSION: Pulsed dye laser and AFL treatments for surgical scar provide significant improvement. Pulsed dye laser was more effective in color of scar compared with AFL, which showed marked improvement in the contour of scar. Overall improvement was not statistically different in the Vancouver Scar Scale.

Clinically relevant humanized mouse models of metastatic prostate cancer facilitate therapeutic evaluation.

There is tremendous need for improved prostate cancer (PCa) models. The mouse prostate is anatomically and developmentally different from the human prostate and does not spontaneously form tumors. Genetically engineered mouse models lack the heterogeneity of human cancer and rarely establish metastatic growth. Human xenografts are an alternative but must rely on an immunocompromised host. Therefore, we generated PCa murine xenograft models with an intact human immune system (huNOG and huNOG-EXL mice) to test whether humanizing tumor-immune interactions would improve modeling of metastatic PCa and the impact of androgen receptor-targeted and immunotherapies. These mice maintain multiple human immune cell lineages, including functional human T-cells and myeloid cells. Implications: To our knowledge, results illustrate the first model of human PCa that has an intact human immune system, metastasizes to clinically relevant locations, responds appropriately to standard-of-care hormonal therapies, and can model both an immunosuppressive and checkpoint-inhibition responsive immune microenvironment.

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.

PIKfyve, expressed by CD11c-positive cells, controls tumor immunity.

Cancer treatment continues to shift from utilizing traditional therapies to targeted ones, such as protein kinase inhibitors and immunotherapy. Mobilizing dendritic cells (DC) and other myeloid cells with antigen presenting and cancer cell killing capacities is an attractive but not fully exploited approach. Here, we show that PIKFYVE is a shared gene target of clinically relevant protein kinase inhibitors and high expression of this gene in DCs is associated with poor patient response to immune checkpoint blockade (ICB) therapy. Genetic and pharmacological studies demonstrate that PIKfyve ablation enhances the function of CD11c+ cells (predominantly dendritic cells) via selectively altering the non-canonical NF-κB pathway. Both loss of Pikfyve in CD11c+ cells 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 regulates the function of CD11c+ cells, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.

The basic chromospheres of skin that might not be differentiated visually: observations on aneurysmal fibrous histiocytomas and malignant melanomas.

AIM: Aneurysmal fibrous histiocytoma (AFH) is a variant of fibrous histiocytoma, which has a cleft-like cavernous blood-filled space in the tumor. It appears as a single reddish black tumor with variable levels of pain and size from its bleeding. And, it must be differentiated from other similar looking malignant conditions such as malignant melanoma. The visual mimicry of AFH to melanoma was raised by some careful dermatologists, but never be confirmed objectively by colorimetric analysis. MATERIALS, SUBJECTS, AND METHODS: In this study, we simply analyzed conventionally photographed digital images of thirty-seven cases of fibrous histiocytomas, including three AFH cases into colorimetrically useful color space, CIELAB, of which coordinates are L*, a*, and b* representing lightness, red to green, and yellow to blue axis, respectively. In addition, we also analyzed the clinical digital images of seven cases of malignant melanomas. Using statistical package, each coordinates of CIELAB were compared using Wilcoxon rank sum test between AFH and melanomas. The CIELAB coordinates of AFH and non-aneurysmal fibrous histiocytomas were compared statistically as well. RESULTS: Comparing with banal fibrous histiocytomas, the colors of AFH showed significantly smaller a* and b* coordinates (P = 0.008, 0.008, respectively), which implies more green and blue hue of AFH lesion. Rather, they were more like melanomas (P = 0.2839, 0.2040, respectively). As for L*, there were no significant differences for all comparisons. CONCLUSIONS: As a result, more objective analysis of the digital images using colorimetric color space confirmed the visual mimicry of AFH to melanoma.

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.

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.