Overexpression of Teashirt Homolog 2 suppresses cell proliferation and predicts the favorable survival of Lung Adenocarcinoma.

Background: Teashirt homolog 2 (TSHZ2) is essential for maintaining cellular homeostasis and regulating transcription on neoplasia development. However, the regulation of TSHZ2 in lung tumorigenesis and the underlying mechanisms remain unclear. Objective: To evaluate the relationship between TSHZ2 expression in patients' tumor tissue and prognosis in lung adenocarcinoma. Methods: TSHZ2 expression in different lung adenocarcinoma cell lines and human tissue were detected by Western blotting. The effect of TSHZ2 on cell proliferation, apoptosis and migration in lung adenocarcinoma cells was measured by CCK8, colony formation, flowcytometric analyses and wound-healing, respectively. TSHZ2 expression in different lung adenocarcinoma cell lines and human tissue from patients was detected using Western blotting and immunohistochemical staining. We also retrospectively analyzed 226 lung adenocarcinoma patients after surgical resection using immunohistochemical staining, and the association of TSHZ2 expression with the patient survival was evaluated. Results: TSHZ2 was lowly expressed in certain lung adenocarcinoma cell lines (PC9 and B203L), but other cells showed a high expression. Low expression of TSHZ2 was also observed in most lung adenocarcinoma tissues compared with adjacent tissues. Furthermore, we found that the overexpression of TSHZ2 plasmids led to the dramatic inhibition of cell proliferation, colony formation ability, migration and apoptosis induction in PC9 lung adenocarcinoma cells. In contrast, no obvious effect was found when the TSHZ2 expression was down-regulated by si-TSHZ2. An elevated TSHZ2 expression was observed in 155(68.6%) tumor tissues samples of lung adenocarcinoma patients. Notably, the lung adenocarcinoma patients with a high TSHZ2 expression tended to have EGFR mutations less frequently and a preferable prognosis to those with a lower expression. Conclusion: A high TSHZ2 expression inhabited cell proliferation and predicted a better prognosis of lung adenocarcinoma, possibly representing a useful therapeutic target for lung adenocarcinoma.

Detection of varicella-zoster virus in two dermatomes of herpes zoster duplex bilateralis in an immunocompetent host.

An 85-year-old woman with no history of herpes zoster (HZ) presented with a primary lesion of erythema and blistering on her left thigh and a secondary similar lesion on her right chest which had appeared at 4 and 3 days before presentation, respectively. Tzanck smears for both lesions were positive, revealing multinucleated giant cells. Immunochromatography to detect varicella-zoster virus (VZV) antigen (DermaQuick®VZV) showed positive on the left thigh at initial onset but negative on the right chest at subsequent onset. The latter repeatedly tested negative for VZV by DermaQuick®VZV. A skin biopsy of the subsequent onset area revealed giant cells, and inclusion bodies were observed in the epidermis. Immunohistochemical staining with anti-VZV antibody and polymerase chain reaction to detect VZV DNA were positive. The patient was diagnosed with HZ duplex bilateralis and treated with acyclovir. The right thoracic region of the posterior part of the lesion became negative for DermaQuick®VZV. It is thought that expression of viral antigens was suppressed in the right thoracic region, i.e., the late-onset area.

Vasculitis-like herpes zoster in the course of treatment with tofacitinib in ulcerative colitis: An assessment of local viral distribution by RNA in situ hybridization.

A 67-year-old man had taken the janus kinase (JAK) inhibitor, tofacitinib, for ulcerative colitis. He was referred to our department for a refractory ulcer on his lower leg. We suspected vasculitis and performed skin biopsy. Histopathological examination showed multinucleated giant cells in the epidermis and fibrinoid degeneration of small vessels in the upper dermis. Varicella zoster virus (VZV) DNA was detected by polymerase chain reaction and we diagnosed the patient with atypical vasculitis-like herpes zoster. The patient was treated with oral valacyclovir, but the rash persisted and took 2 months to heal. Immunostaining using anti-VZV antibody was positive mainly in epidermal keratinocytes, but was also observed to be positive in cells in the dermis. We further performed RNA in situ hybridization using a VZV ORF9 mRNA probe and clearly showed that the distribution of VZV mRNA extended into the dermis, including the dermal vessel walls and the eccrine sweat glands as well as the epidermis. The internal administration of JAK inhibitors may induce regional widespread VZV infection including vessels and involved in the formation of prolonged vasculitis-like manifestation. RNA in situ hybridization can be a potent tool for detecting the spread of VZV infection in the skin.

Surface material analysis for human papillomavirus detection in nail Bowen's disease caused by HPV type 58.

Over the past few years, cases of human papillomavirus (HPV) infection in nail Bowen's disease have been reported. This disease presents diagnostic challenges due to its similarity to nail malignant melanoma, particularly with respect to the clinical manifestation of black nail streaks. While skin biopsy is usually employed for diagnosis, it is an invasive procedure. We report the case of a 52-year-old healthy Japanese male with a pigmented streak on the nail of the fourth finger of his right hand, which had extended from the central to the lateral nail fold within 4 months. Dermoscopic examination revealed a dark-brown pigmented band with splinter microhemorrhage. Clinically, nail Bowen's disease was suspected. The lesion was excised in strips under local anesthesia. Histopathological examination revealed hyperkeratosis, parakeratosis, papillomatosis, and dyskeratotic cells with atypical nuclei irregularly arranged. Immunohistochemistry using anti-HPV L1 antibody detected HPV-positive cells in the upper epidermis and stratum corneum of the nail matrix. Mucosal high-risk HPV type 58 DNA was detected from brush cytology of the keratotic surface prior to surgery, which was confirmed in formalin-fixed, paraffin-embedded excised samples using polymerase chain reaction (PCR) and subsequent direct DNA sequencing. Our case highlights HPV type 58 as a potential causative agent of nail Bowen's disease and shows that brush cytology of the surface material prior to excision may be a useful and less invasive way for mucosal high-risk HPV detection. PCR analysis of the nail surface could serve as a supplementary diagnostic tool for nail Bowen's disease.

Recent advances in cutaneous HPV infection.

More than 200 types of human papillomavirus (HPV) have been reported to date and have been associated with various dermatological diseases. Among dermatological diseases, viral verrucae are the most commonly reported to be associated with HPV. Epidermodysplasia verruciformis (EV) consists of three types: typical EV is an autosomal recessive genetic disorder with TMC6/TMC8 gene mutations, atypical EV develops due to various gene mutations that cause immunodeficiency, and acquired EV develops due to acquired immunodeficiency. Generalized verrucosis differs from EV in that it involves numerous verrucous nodules (mainly on the limbs), histopathologically no blue cells as seen in EV, and infection with cutaneous α-HPVs as well as ß-HPVs. HPV-induced skin malignancies include squamous cell carcinoma (SCC) caused by ß-HPV (especially HPV types 5 and 8) in EV patients, organ transplant recipients, and healthy individuals, and SCC of the vulva and nail unit caused by mucosal high-risk HPV infection. Carcinogenesis of ß-HPV is associated with sunlight. Mucosal high-risk HPV-associated carcinomas may also be sexually transmitted. We focused on Bowen's disease of the nail, which has been the subject of our research for a long time and has recently come to the fore in the field of dermatology.

Possibly the first case of onychomycosis by Fusarium lactis: Case presentation and literature review of onychomycosis by Fusarium species.

Fusarium species (spp.) is frequently found in soil and plant residues and on plant bodies in all climatic zones worldwide. Although there have been few reports of onychomycosis caused by Fusarium spp., it is characterized by drug sensitivity and other characteristics. Here, we report what may be the first case of onychomycosis caused by Fusarium lactis. We analyzed the mycology and characterized previously reported cases of onychomycosis caused by Fusarium spp. A 73-year-old otherwise healthy woman presented with discoloration and thickening of her right thumbnail with paronychia. Direct microscopy revealed unevenly swollen hyphae, and a Grocott-stained nail specimen showed septate hyphae. Based on the morphological features and gene analysis of fungus isolated from the nail, we diagnosed onychomycosis caused by F. lactis belonging to Fusarium fujikuroi species complex. Partial nail removal and topical application of 1% luliconazole solution resolved the condition in 6 months. Minimum inhibitory concentrations for isolated F. lactis showed high sensitivity to luliconazole but not itraconazole or terbinafine. The isolated F. lactis was temperature-sensitive. A search of the literature revealed 57 cases of onychomycosis caused by Fusarium spp. with delineated clinical characteristics. Since those cases were investigated using morphological and/or molecular methods, we analyzed them by species complex as well as species. Onychomycosis caused by Fusarium spp. is predominantly found on the big toe, with Fusarium solani species complex and Fusarium oxysporum species complex accounting for over 70% of cases. Infection of only one digit with paronychia is a characteristic clinical manifestation of onychomycosis caused by Fusarium spp. Since there has been an increase in instances of molecular determination of Fusarium spp., it is deemed necessary to clarify its clinical and fungal nature. Due to its characteristic drug sensitivity and temperature-sensitive nature, new treatments are expected to be developed.

Schimmelpenning-Feuerstein-Mims syndrome induced by HRAS Gly12Ser somatic mosaic mutation: Case report and literature review.

Schimmelpenning-Feuerstein-Mims syndrome (SFMS), an epidermal nevus disease, features skin lesions including craniofacial nevus sebaceous and extracutaneous anomalies (e.g. brain, eye, and bone). Recent genetic studies implicate HRAS, KRAS, and NRAS genes in somatic mutations. Our case, a 48-year-old man, presented with nevus sebaceous on the scalp; pigmented skin lesions on the right side of his neck, back, and chest along the Blaschko lines; a history of epilepsy; and mild intellectual disability. Accordingly, SFMS was suspected. DNA analysis of nevus sebaceous skin and peripheral blood leukocytes showed a pathogenic HRAS variant NM_005343.4:c.34G > A p.(Gly12Ser) in biopsy specimens from different skin layers but not blood, indicating somatic mosaic mutation. Until now, the HRAS p.(Gly12Ser) mutation has been reported in somatic RASopathies but not SFMS. The authors report this mutation in a case of SFMS, review another 15 cases of SFMS, and discuss HRAS c.34G > A p.(Gly12Ser) somatic mutations. RAS mutations of somatic RASopathies share activating hotspot mutations found in cancers, and produce different phenotypes depending on the developmental stage at which the somatic mutations occur.

Polypoid Basal Cell Carcinoma on the Nose Tip.

Basal cell carcinoma (BCC) is usually seen on the face as a pigmented nodule. We herein report a patient who presented with a polypoid BCC on the nose tip. Clinically, we suspected adnexal tumor; however, the findings of dermoscopy were consistent with that of BCC. Although the tumor was excised at the stalk, it was completely resected. Since the clinical manifestation was characteristic, we reviewed previously reported polypoid BCCs and found that this tumor can occur at any site, including the trunk and inguinal region, which are not preferential sites for ordinary BCC. There have been no reports of polypoid BCC on the nasal tip. The initial diagnoses varied, including adnexal tumors, and dermoscopic examinations proved useful for suspecting polypoid BCC. Histopathologically, the tumor cells in the resected specimens were within the polypoid area. Although BCC is a common tumor, polypoid BCC has distinct clinical features, and we should keep this rare subtype in mind.

Zonarol Protected Liver from Methionine- and Choline-Deficient Diet-Induced Nonalcoholic Fatty Liver Disease in a Mouse Model.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases with no approved treatment. Zonarol, an extract from brown algae, has been proven to have anti-inflammatory and antioxidant effects. In this study, we investigated the role of zonarol in the progression of methionine- and choline-deficiency (MCD) diet-induced NAFLD in mice. After oral treatment with zonarol, a lighter body weight was observed in zonarol group (ZG) mice in comparison to control group (CG) mice. The NAFLD scores of ZG mice were lower than those of CG mice. Hepatic and serum lipid levels were also lower in ZG mice with the reduced expression of lipid metabolism-related factors. Furthermore, ZG mice showed less lipid deposition, less inflammatory cell infiltration and lower inflammatory cytokine levels in comparison to CG mice. Moreover, the numbers of 8-hydroxy-20-deoxyguanosine (8-OHdG)-positive hepatocytes and levels of hepatic and serum thiobarbituric acid reactive substances (TBARS) were significantly lower in comparison to CG mice. The expression levels of nuclear factor erythroid 2 related factor 2 (Nrf2), as well as its upstream and downstream molecules, changed in ZG mice. Zonarol could prevent the progression of NAFLD by decreasing inflammatory responses, oxidative stress and improving lipid metabolism. Meanwhile the Nrf2 pathway may play an important role in these effects.

PRDX4 Improved Aging-Related Delayed Wound Healing in Mice.

Aging-related delayed wound healing is an issue of concern worldwide. Oxidative stress is involved in wound healing. Antioxidative enzymes have various roles in this process. PRDX4, a member of the PRDX family, is upregulated after injury. To investigate the effects of PRDX4 on aging-related wound healing, we subjected C57BL/6J (wild-type), human Prdx4‒transgenic (i.e., hPrdx4+/+), Prdx4-knockout (i.e., Prdx4-/y) mice of three age groups (young, adult, and aged) to skin wound formation. The overexpression of PRDX4 accelerated wound healing in adult and aged mice but not in young mice. Aged hPrdx4+/+ mice showed reduced oxidative stress and inflammation, lower numbers of neutrophils, increased macrophage infiltration, increased angiogenesis, and increased GF levels. The granulation tissue of adult and aged hPrdx4+/+ mice was richer in fibroblasts than that in the matched wild-type mice. PRDX4 deficiency was associated with mortality in adult and aged mice. In vitro, the overexpression of PRDX4 promoted the proliferation and migration of fibroblasts derived from adult or aged mice and made fibroblasts more resistant to the cytotoxicity of hydrogen peroxide. PRDX4 is essential for wound healing and can improve the healing process from multiple aspects, suggesting that it may be very beneficial to wound treatment, especially for the elderly.

Acupuncture improved lipid metabolism by regulating intestinal absorption in mice.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD), in which abnormal lipid metabolism plays an important role in disease progression, has become a pandemic. Abnormal lipid metabolism, for example an increased fat intake, has been thought to be an initial factor leading to NAFLD. The small intestine is the main site of dietary lipid absorption. A number of clinical trials have shown that acupuncture has positive effects in the regulation of lipid metabolism, which is closely associated with the progression of NAFLD. We therefore hypothesized that, acupuncture can improve the conditions of NAFLD by regulating intestinal absorption of lipid. AIM: To study the role of acupuncture treatment in the improvement of metabolic syndrome secondary to NAFLD by mouse model. METHODS: 8-wk-old male C57BL/6J mice were fed a methionine- and choline-deficient diet for 3 wk. Then, all mice were separated randomly into acupoints group (AG) or non-acupoints group (NG) with high fat diet feeding. Needling treatment was performed at Zu san li, Guan yuan and Yong quan acupoints as acupuncture treatment to AG mice while non-acupoints place to NG mice. Finally, mice were anesthetized with an injection of ketamine-medetomidine and euthanized by exsanguination. RESULTS: An apparent improvement of obesity was found in AG mice after acupuncture treatment. In AG mice, the body weight was much lower (22.6 ± 1.2 g vs 28.1 ± 1.0 g, P < 0.005) in comparison to NG mice. The length of small intestine in AG mice was significantly shorter (26.7 ± 2.3 cm vs 32.7 ± 2.7 cm, P < 0.005). A large amount of chyme was observed in the lumen of the AG small intestine. The expression of microsomal triglyceride transfer protein, apolipoprotein B and apolipoprotein C2 was downregulated. Triacylglycerols (TGs), total cholesterol and nonesterified fatty acid (NEFA) levels of the small intestinal tissue were significantly higher in AG mice, but the serum TGs and NEFA levels were reduced in AG mice. CONCLUSION: These results indicate that acupuncture at Zu san li, Guan yuan and Yong quan suppressed lipid absorption by downregulating the expression of apolipoproteins in the small intestine.

Overexpression of PRDX4 Modulates Tumor Microenvironment and Promotes Urethane-Induced Lung Tumorigenesis.

Peroxiredoxin 4 (PRDX4), initially reported as an antioxidant, is overexpressed in lung cancer and participates in its progression. However, its role in the urethane-induced lung tumor model is undetermined. The aim of this study was to investigate the effect of PRDX4 overexpression on carcinogen-induced lung tumor development. Human PRDX4 overexpression transgenic (Tg) mice (hPRDX4+/+ ) and non-Tg mice were intraperitoneally injected with urethane to induce lung tumor. After 6 months, tumor formation was compared between groups and possible mechanisms for the difference in tumor development were investigated. The serum and lung PRDX4 expressions were enhanced after urethane stimulation in Tg mice. Both the average number of tumors (≥0.5 mm) and tumor diameter per mouse in the Tg group were significantly larger than in non-Tg controls, while body weight was lower in the Tg group. Compared with non-Tg controls, tumor cell proliferation was enhanced, while tumor cell apoptosis was suppressed in Tg mice. Systemic oxidative stress and oxidative stress in lung tumors were inhibited by PRDX4 overexpression. The balance of prooxidant enzymes and antioxidant enzymes was also shifted to a decreased level in Tg tumor. In lung tumor tissue, the density of microvessel penetrated into tumor was higher in the Tg group; macrophage infiltration was enhanced in Tg tumors, while there was no difference in T lymphocyte infiltration; the expressions of cytokines, including interleukin-1 beta (IL-1ß) and matrix metallopeptidase 9 (MMP9), were elevated in Tg tumors, which resulted from enhanced phosphorylation of nuclear factor-κB p65 (NF-κB p65) and c-Jun, respectively. In conclusion, PRDX4 overexpression modulated tumor microenvironment and promoted tumor development in the mouse urethane-induced lung cancer model.

Peroxiredoxin 4 promotes embryonal hepatoblastoma cell migration but induces fetal cell differentiation.

Hepatoblastoma (HB) is the leading primary hepatic malignancy in children and likely emerges due to failure of hepatic progenitor cells to properly differentiate. The peroxiredoxin (PRDX) family is frequently linked to cancer. In our previous study, we demonstrated that expression of the only secreted family member, PRDX4, was correlated with hepatocellular carcinoma. The aim of this new study was to investigate PRDX4's role in HB. We collected 87 HB specimens and performed PRDX4 immunohistochemistry staining. Clinical analysis was conducted and the effect of PRDX4 overexpression on two HB cell lines (Huh6 and HepG2) was also examined. Clinical data revealed elevated PRDX4 expression in embryonal component was correlated with advanced stage (IV) and metastasis. In comparison, increased PRDX4 expression in fetal component was associated with well differentiation. In vitro experiments showed PRDX4 overexpression enhanced migration in embryonal-like HB cells (Huh6), which was accompanied by epithelial-mesenchymal transition (EMT). By contrast, PRDX4 overexpression inhibited proliferation, decreased stemness markers, and increased hepatic markers in fetal-like HB cells (HepG2), which indicated induction of tumor cell differentiation. In conclusion, PRDX4 promotes embryonal hepatoblastoma cell migration but induces fetal cell differentiation. It can be adopted as an important marker for HB prognosis and a potential treatment target.

Acupuncture on ST36, CV4 and KI1 Suppresses the Progression of Methionine- and Choline-Deficient Diet-Induced Nonalcoholic Fatty Liver Disease in Mice.

Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide, and its treatment remain a constant challenge. A number of clinical trials have shown that acupuncture treatment has beneficial effects for patients with NAFLD, but the molecular mechanisms underlying its action are still largely unknown. In this study, we established a mouse model of NAFLD by administering a methionine- and choline-deficient (MCD) diet and selected three acupoints (ST36, CV4, and KI1) or nonacupoints (sham) for needling. We then investigated the effects of acupuncture treatment on the progression of NAFLD and the underlying mechanisms. After two weeks of acupuncture treatment, the liver in the needling-nonapcupoint group (NG) mice appeared pale and yellowish in color, while that in the needling-acupoint group (AG) showed a bright red color. Histologically, fewer lipid droplets and inflammatory foci were observed in the AG liver than in the NG liver. Furthermore, the expression of proinflammatory signaling factors was significantly downregulated in the AG liver. A lipid analysis showed that the levels of triglyceride (TG) and free fatty acid (FFA) were lower in the AG liver than in the NG liver, with an altered expression of lipid metabolism-related factors as well. Moreover, the numbers of 8-hydroxy-2'-deoxyguanosine (8-OHdG)-positive hepatocytes and levels of hepatic thiobarbituric acid reactive substances (TBARS) were significantly lower in AG mice than in NG mice. In line with these results, a higher expressions of antioxidant factors was found in the AG liver than in the NG liver. Our results indicate that acupuncture repressed the progression of NAFLD by inhibiting inflammatory reactions, reducing oxidative stress, and promoting lipid metabolism of hepatocytes, suggesting that this approach might be an important complementary treatment for NAFLD.