The hematopoietic U937 cells are able to differentiate into monocytes, macrophages, or osteoclasts when stimulated, respectively, with vitamin D3 (VD3), phorbol 12-myristate 13-acetate (PMA) or PMA plus VD3. We have previously demonstrated that magnesium (Mg) strongly potentiates the osteoclastic differentiation of U937 cells. In this study, we investigated whether such an effect may be ascribed to a capacity of Mg to modulate the monocyte differentiation of U937 cells and/or to an ability of Mg and VD3 to act directly and independently on the early phases of the osteoclastic differentiation. To address this issue, we subjected U937 cells to an individual and combined treatment with Mg and VD3 and then we analyzed, by flow cytometry and quantitative real-time polymerase chain reaction, the expression of a number of genes related to the early phases of the differentiation pathways under consideration. The results obtained indicated that Mg favors the monocyte differentiation of U937 cells induced by VD3 and at the same time, Mg contrasts the inhibitory effect that VD3 exerts on the osteoclastic differentiation in the absence of PMA. The crucial and articulated role played by Mg in diverse pathways of the osteoclastic differentiation of U973 cells is emphasized.

Keywords: CTSO; DSCT1; KLF4; MAFB; MITF; NFATC1; TFE3; TRAP; U937 cells; Vitamin D3; magnesium; monocyte differentiation; osteoclast differentiation.

Renal tumors are one of the most diverse groups of tumors in pathology. Many emerging and important entities have been described recently. Here, we describe a series of renal tumors occurring in adult patients, with distinct histologic features, and with a striking resemblance to gonadal sex cord-stromal tumors. Patients were three males and three females aged 39-82 years; tumor size ranged from 0.9 to 3.6 cm. Five tumors were organ-confined, while one case had a focal perinephric invasion. No aggressive behavior was noted. Microscopically, all the tumors were composed of loose or compact tubular structures with elongated or angulated shapes. The tumor cells were cylindrical or cuboidal, with pale eosinophilic cytoplasm, irregular nuclear membranes, and ISUP/WHO grade 2-3 nuclei. The stroma showed focal or prominent collagen deposition with prominent basement membrane-like material. In all cases, the tumor cells were positive for PAX8, CD10, and vimentin and retained positivity for FH and SDHB. Cathepsin K and AMACR were variably positive. Tumors were negative for HMB45, Melan A, TFE3, SF1, inhibin, calretinin, ER, PR, CD117, OCT3/4, SALL4, ALK, and WT1. Molecular studies showed no abnormalities in TFEB, TFE3, or FH genes. In 3/4 tested cases, mutation of the NF2 gene was present. In all the tested male cases, loss of the Y chromosome was found. In the relatively short follow-up, these tumors appear to have indolent behavior. This study expands the clinicopathologic diversity of renal cell tumors by describing a series of potentially novel tumors morphologically resembling gonadal sex-stromal tumors, with negativity for sex cord-stromal markers. Potential relationship to recently described biphasic hyalinizing psammomatous renal cell carcinoma is discussed.

Keywords: Biphasic hyalinizing psammomatous renal cell carcinoma; Gonadoblastoma-like; Kidney; NF2 mutation; Renal cell carcinoma; Sex cord-stromal tumor-like.

TFE3-translocation renal cell carcinoma (TFE3-tRCC) is a rare and heterogeneous subtype of kidney cancer with no standard treatment for advanced disease. We describe comprehensive molecular characteristics of 63 untreated primary TFE3-tRCCs based on whole-exome and RNA sequencing. TFE3-tRCC is highly heterogeneous, both clinicopathologically and genotypically. ASPSCR1-TFE3 fusion and several somatic copy number alterations, including the loss of 22q, are associated with aggressive features and poor outcomes. Apart from tumors with MED15-TFE3 fusion, most TFE3-tRCCs exhibit low PD-L1 expression and low T-cell infiltration. Unsupervised transcriptomic analysis reveals five molecular clusters with distinct angiogenesis, stroma, proliferation and KRAS down signatures, which show association with fusion patterns and prognosis. In line with the aggressive nature, the high angiogenesis/stroma/proliferation cluster exclusively consists of tumors with ASPSCR1-TFE3 fusion. Here, we describe the genomic and transcriptomic features of TFE3-tRCC and provide insights into precision medicine for this disease.

The stress of the Golgi apparatus is an autoregulatory mechanism that is induced to compensate for greater demand in the Golgi functions. No examples of Golgi stress responses due to physiological stimuli are known. Furthermore, the impact on this organelle of viral infections that occupy the vesicular transport during replication is unknown. In this work, we evaluated if a Golgi stress response is triggered during dengue and Zika viruses replication, two flaviviruses whose replicative cycle is heavily involved with the Golgi complex, in vertebrate and mosquito cells. Using GM-130 as a Golgi marker, and treatment with monensin as a positive control for the induction of the Golgi stress response, a significant expansion of the Golgi cisternae was observed in BHK-21, Vero E6 and mosquito cells infected with either virus. Activation of the TFE3 pathway was observed in the infected cells as indicated by the translocation from the cytoplasm to the nucleus of TFE3 and increased expression of pathway targeted genes. Of note, no sign of activation of the stress response was observed in CRFK cells infected with Feline Calicivirus (FCV), a virus released by cell lysis, not requiring vesicular transport. Finally, dilatation of the Golgi complex and translocation of TFE3 was observed in vertebrate cells expressing dengue and Zika viruses NS1, but not NS3. These results indicated that infections by dengue and Zika viruses induce a Golgi stress response in vertebrate and mosquito cells due to the increased demand on the Golgi complex imposed by virion and NS1 processing and secretion.

Cutaneous fibromyxoid neoplasms (CFMN) comprise a vast category of benign and malignant tumors that include, but are not limited to, low-grade fibromyxoid sarcoma, myxofibrosarcoma, myxoid dermatofibrosarcoma protuberans, myxoid solitary fibrous tumor, and myxoid neurofibroma with differing implications for treatment and prognosis. Herein, a case of CFMN arising as a painless, slow-growing, flesh-colored forearm mass in a 53-year-old female is presented. The neoplasm was composed of copious myxoid material with banal spindle cells, exhibiting mild hyperchromasia, dissecting the dermal collagen table. Focal perivascular accentuation of spindle cells was identified in the absence of vasoformative features. Immunohistochemically, lesional cells were strongly and diffusely positive for CD34 and multifocally for Factor XIIIa and EMA while negative for CD31, ERG, FLI-1, D2-40, SMA, Desmin, S100, HMB-45, STAT6, MUC4, and keratins. RNA and DNA-sequencing identified a YAP1::TFE3 fusion transcript that were subsequently corroborated by fluorescence in situ hybridization (FISH) and immunohistochemistry for [TFE3 (Xp11.23) locus rearrangement and strong, diffuse TFE3 immunoreactivity, respectively]. To date, the YAP1::TFE3 fusion has only been identified in a subset of epithelioid hemangioendotheliomas and clear cell stromal tumors of the lung. This is the first report of a CFMN featuring a YAP1::TFE3 fusion YAP1 exon 1 and TFE3 exon 4. The morphologic findings are unlike those previously described for epithelioid hemangioendothelioma and suggest that this neoplasm may represent a yet unclassified or novel CFMN entity. Although the patient is one-year status post-surgical excision with no evidence of clinical recurrence, the clinical behavior of this novel entity remains to be fully characterized. This article is protected by copyright. All rights reserved.

Keywords: Cutaneous fibromyxoid neoplasm; YAP1::TFE3 gene fusion; molecular genetics.

Translocation renal cell carcinoma (tRCC) is a poorly characterized subtype of kidney cancer driven by MiT/TFE gene fusions. Here, we define the landmarks of tRCC through an integrative analysis of 152 patients with tRCC identified across genomic, clinical trial, and retrospective cohorts. Most tRCCs harbor few somatic alterations apart from MiT/TFE fusions and homozygous deletions at chromosome 9p21.3 (19.2% of cases). Transcriptionally, tRCCs display a heightened NRF2-driven antioxidant response that is associated with resistance to targeted therapies. Consistently, we find that outcomes for patients with tRCC treated with vascular endothelial growth factor receptor inhibitors (VEGFR-TKIs) are worse than those treated with immune checkpoint inhibitors (ICI). Using multiparametric immunofluorescence, we find that the tumors are infiltrated with CD8⁺ T cells, though the T cells harbor an exhaustion immunophenotype distinct from that of clear cell RCC. Our findings comprehensively define the clinical and molecular features of tRCC and may inspire new therapeutic hypotheses.

Keywords: MITF; NRF2; TFE3; TFEB; VEGFR; genomics; immune checkpoint inhibition; immunotherapy; oxidative stress; translocation renal cell carcinoma.

The mortality rates among patients who initially survive sepsis are, in part, associated with a high risk of secondary lung infections and respiratory failure. Given that phagolysosomes are important for intracellular killing of pathogenic microbes, we investigated how severe lung infections associated with post-sepsis immunosuppression affect phagolysosome biogenesis. In mice with P. aeruginosa-induced pneumonia, we found a depletion of both phagosomes and lysosomes, as evidenced by decreased amounts of microtubule associated protein light chain 3-II (LC3-II) and lysosomal-associated membrane protein (LAMP1). We also found a loss of transcription factor E3 (TFE3) and transcription factor EB (TFEB), which are important activators for transcription of genes encoding autophagy and lysosomal proteins. These events were associated with increased expression of ZKSCAN3, a repressor for transcription of genes encoding autophagy and lysosomal proteins. Zkscan3^-/- mice had increased expression of genes involved in the autophagy-lysosomal pathway along with enhanced killing of P. aeruginosa in the lungs, as compared to wild-type mice. These findings highlight the involvement of ZKSCAN3 in response to severe lung infection, including susceptibility to secondary bacterial infections due to immunosuppression.

The organelle of eukaryotes is a finely regulated system. Once disturbed, it activates the specific autoregulatory systems, namely, organelle autoregulation. Among which, the Golgi stress response accounts for one. When the abundance and capacity of the Golgi apparatus are insufficient compared with cellular demand, the Golgi stress response is activated to enhance the function of the Golgi apparatus. Although the molecular mechanism of the Golgi stress response has not been well characterized yet, it seems to be an important part of the mammalian stress response. In this review, we discuss the current status of research on the six pathways of the mammalian Golgi stress response (the TFE3, heat shock protein 47, CREB3, E26 transformation specific, proteoglycan, and mucin pathways), which regulate the general function of the Golgi apparatus, anti-apoptosis, pro-apoptosis, proteoglycan glycosylation, and mucin glycosylation, respectively.

Keywords: CREB3; ETS; HSP47; PG; TFE3; mucin pathway.

Ossifying fibromyxoid tumor (OFMT) is a rare mesenchymal neoplasm of uncertain line of differentiation that can be subdivided into typical, atypical, and malignant tumors. Cytogenetically, OFMT is characterized by recurrent gene rearrangement involving PHF1 in up to 85% of cases. The most common PHF1 fusion partner is EP400, present in approximately half of cases. Most recently, a novel fusion of PHF1-TFE3 was identified in about 10% of PHF1-rearranged OFMTs. Herein, we report a unique case of PHF1-TFE3 fusion atypical OFMT with prominent collagenous rosettes. A 50-year-old male patient presented with a slowly growing, painless mass in the right foot for 4 years. Gross examination showed a 3.5-cm, subcutaneous well-circumscribed, lobulated mass. Microscopic examination revealed a well-demarcated but un-encapsulated tumor without a peripheral bony shell. The neoplasm was composed of mildly atypical spindle to ovoid cells with increased mitosis (2 mitoses per 10 high-power fields) arranged in a multinodular manner within a fibromyxoid stroma, which contained numerous of small, irregular collagenous rosettes surrounded by radiating growth of tumor cells. The neoplastic cells were diffusely positive for TFE3 and CD10. RNA sequencing revealed an in-frame fusion between PHF1 exon 12 and TFE3 exon 7. Subsequent Fluorescence in-situ hybridization analyses demonstrated positive for rearrangements of both the PHF1 and TFE3 loci. The patient was free of disease at 63 months' follow-up. Our case exhibits atypical features and prominent collagenous rosettes, expanding the morphological spectrum of OFMT with PHF1-TFE3 fusion.

Keywords: Atypical; Fusion gene; Ossifying fibromyxoid tumor; PHF1; TFE3.

Objective: To investigate the clinicopathological and molecular features, diagnosis and differential diagnosis of TFE3-rearranged epithelioid hemangioendothelioma (EHE). Methods Two cases of TFE3-rearranged EHE arising from soft tissues, diagnosed by the Pathology Department of the First Affiliated Hospital of Nanjing Medical University from 2013 to 2020 were observed. EnVision method was used for immunophenotyping, fluorescence in situ hybridization (FISH) was used to test TFE3 gene rearrangements and WWTR1-CAMTA1 fusion gene,and next-generation sequencing (NGS) was used to delineate the fusion transcripts. Results: Details of these two cases were as follows: case 1, male, 51 years old, with tumor in the right temporal region; case 2, female, 42 years old, with tumor in the right neck. The tumors showed progressive painless enlargement. Grossly, the tumor of case 1 was multinodular with unclear boundary and grayish red cut surface, while the tumor of case 2, originating from a vein, appeared as a firm, tan mass within vessel wall. Microscopically, both tumors showed moderate cellularity and were consisted of plump, epithelioid, or histiocytoid cells with eosinophilic cytoplasm and mild-to-moderate nuclear pleomorphism. Most of the tumor cells were arranged in solid or alveolar growth patterns, while some tumor cells showed intraluminal papillary growth pattern in case 1 and anastomosing vascular channels and extramedullary hematopoiesis in case 2. Immunohistochemically, the tumor cells showed diffuse positivity for CD31, CD34, ERG, and TFE3. FISH revealed TFE3 break-apart signals in two cases, but WWTR1-CAMTA1 gene fusion was not detected. NGS identified YAP1 (exon1)-TFE3 (exon6) fusion gene in case 2. Clinical follow-up information was available in both cases for a follow-up period of 15 and 59 months respectively. Patient 1 had a relapse 22 months after surgery, and was currently alive with the tumor. Patient 2 remained disease-free. Conclusions: TFE3-rearranged EHE is a rare molecular subtype of EHE, with accompanying characteristic morphologic features. However the morphologic spectrum remains under-recognized, and more experience is needed. Immunohistochemical and molecular examinations are helpful for the diagnosis and differential diagnosis of the disease.

目的： 探讨TFE3重排的上皮样血管内皮瘤（EHE）的临床病理学特征、分子特点、诊断及鉴别诊断。 方法： 收集2013—2020年南京医科大学第一附属医院病理科诊断的软组织TFE3重排的EHE共2例，采用EnVision法进行免疫组织化学染色，荧光原位杂交（FISH）法检测TFE3基因断裂重排及WWTR1-CAMAT1基因融合情况，二代测序检测其融合转录本。 结果： 患者2例，例1男，51岁，右颞部肿瘤；例2女，42岁，右颈部肿瘤。临床表现均为肿块无痛性进行性增大。大体检查，例1呈结节状生长，边界不清，切面灰红；例2在静脉壁内生长，切面淡褐色。镜下，2例均为中等细胞密度，胞质丰富嗜酸，似泡沫样或组织细胞样形态，核轻至中度多形性。大多数肿瘤细胞呈实性或腺泡状排列，但例1中观察到腔内乳头状生长方式，例2中观察到血管吻合沟通区域和髓外造血现象。免疫组织化学上，肿瘤细胞强阳性表达CD31（2/2）、CD34（2/2）、ERG（2/2）和TFE3（2/2）。FISH示TFE3基因断裂（2/2），未见WWTR1-CAMAT1基因融合（0/2）。二代测序示例2出现YAP1（exon1）-TFE3（exon6）融合。2例均获随访，随访时间15~59个月，例1术后22个月复发，目前带瘤生存，例2未复发。 结论： TFE3重排的EHE是一种少见的分子亚型，有特殊的形态学表现，但也可能有少见的形态学谱系；免疫组织化学及分子病理学辅助检查有助于疾病的诊断及鉴别诊断。.

Background and purpose: Necrosis of random-pattern skin flaps limits their clinical application. Helix B surface peptide (HBSP) protects tissues from ischemia-reperfusion injury; however, the short plasma half-life of HBSP limits its applications. Cyclic helix B peptide (CHBP) was synthesized in the present study, and the role of CHBP in flap survival and the underlying mechanism were investigated.

Experimental approach: Flap viability was evaluated by survival area analysis, laser doppler blood flow, and histological analysis. RNA sequencing was used to identify the mechanisms relevant to the role of CHBP. Western blotting, real-time quantitative PCR, immunohistochemistry, and immunofluorescence were used to assay the levels of autophagy, oxidative stress, pyroptosis, necroptosis, and molecules related to the adenosine 5'-monophosphate-activated protein kinase (AMPK)-transient receptor potential mucolipin 1 (TRPML1)-calcineurin signaling pathway.

Key results: The results indicated that CHBP promoted the survival of random-pattern skin flaps. The results of RNA sequencing analysis indicated that autophagy, oxidative stress, pyroptosis, and necroptosis were involved in the ability of CHBP to promote skin flap survival. Restoration of autophagy flux and enhanced resistance to oxidative stress contributed to inhibition of pyroptosis and necroptosis. Increased autophagy and inhibition of oxidative stress in the ischemic flaps are regulated by transcription factor E3 (TFE3). A decrease in the levels of TFE3 caused a reduction in autophagy flux and accumulation of ROS and eliminated the protective effect of CHBP. Moreover, CHBP regulated the activity of TFE3 via the AMPK-TRPML1-calcineurin signaling pathway.

Conclusion and implications: CHBP promotes skin flap survival by upregulating autophagy and inhibiting oxidative stress in the ischemic flap and may have potential clinical applications.

Keywords: Autophagy; CHBP; Oxidative stress; Random skin flaps; TFE3.

Background: Perivascular epithelioid cell tumors (PEComas) are rare, mesenchymal neoplasms composed of epithelioid cells exhibiting myogenic and melanocytic differentiation. The uterus is an infrequent site of involvement. The most common histopathologic mimics include leiomyosarcoma, endometrial stromal sarcoma, undifferentiated uterine sarcoma, and malignant melanoma. Rendering an accurate histopathologic diagnosis is essential, owing to the prognostic and therapeutic implications.

Case: A 65-years-old post-menopausal woman presented with post-menopausal bleeding, abdominal pain, and heaviness for the last four months. Ultrasound abdomen revealed a large uterine mass replacing the endometrial cavity. She underwent a total abdominal hysterectomy with bilateral salpingo-oophorectomy.

Result: Microscopically, a circumscribed tumor with tumor cells arranged in sheets and interlacing fascicles, with interspersed fine capillary network, was seen. The individual tumor cells were epithelioid to spindle with moderate pleomorphism, round nuclei, vesicular chromatin, prominent macronucleoli, and moderate cytoplasm. Mitosis was 2-3/50 HPFs. On immunohistochemistry, tumor cells were positive for HMB-45, Melan-A, and smooth muscle actin and were negative for h-caldesmon, TFE3, S-100, CD10, and pan-cytokeratin. Based on the histopathologic and immunohistochemical features, a final diagnosis of malignant uterine PEComa was rendered.

Conclusions: This index report describes the characteristic histopathologic and immunohistochemical features of malignant uterine PEComa and highlights the salient features that distinguish it from other commonly encountered histopathologic mimics.

Keywords: Cathepsin K; HMB-45; PEComa; PNL2; histopathology; immunohistochemistry; perivascular epithelioid cell tumor; uterine PEComa.

Background: Accumulating evidence shows that autophagy plays a vital role in tumor occurrence, development, and metastasis and even determines tumor prognosis. However, little is known about its role in papillary thyroid carcinoma (PTC) or the potentially oncogenic role of TFE3 in regulating the autophagy-lysosome system.

Methods: Immunohistochemistry and quantitative real-time PCR (qRT-PCR) were used to examine the expression of TFE3, P62/SQSTM1, and LC3 in PTC and paracancerous tissues. TFE3, P62/SQSTM1, LC3, cathepsin L (CTSL), and cathepsin B (CTSB) were evaluated using Western blot analysis. After inducing TFE3 overexpression by plasmid or TFE3 downregulation by small interfering RNA (siRNA) transfection, MTT, wound healing, and cell migration and invasion assays were used to verify the effects on invasion, migration, and the levels of autophagy-lysosome system-related proteins such as P62/SQSTM1, LC3, CTSL, and CTSB.

Results: TFE3 was overexpressed in PTC tissues compared with paracancerous tissues. Analysis of the clinicopathological characteristics of PTC patients showed that high TFE3 expression was significantly correlated with lymph node metastasis. TFE3 overexpression in the PTC cell lines KTC-1 and BCPAP promoted proliferation, invasion, and migration, while TFE3 knockdown had the opposite effects. Furthermore, we identified a positive relationship among the expression levels of TFE3, P62/SQSTM1, LC3, CTSL, and CTSB. We found that silencing TFE3 inhibited the expression of P62/SQSTM1, LC3, CTSL, and CTSB in PTC cells. However, TFE3 overexpression had the opposite effects.

Conclusions: The present study provided evidence for the underlying mechanisms by which TFE3 induces autophagy-lysosome system activity in PTC.

Renal cell carcinoma with leiomyomatous stroma is a rare and poorly described histopathological entity. Here we report a unique case with osseous metaplasia, in a 31-year-old man recently diagnosed with a tuberous sclerosis complex (TSC2 gene mutation). Partial nephrectomy was performed. Histologically, the epithelial component was made up of papillary and alveolar structures with clear to eosinophilic cytoplasm, and basally located nuclei. The cells are surrounded by an abundant smooth muscle stroma with focally osseous metaplasia. The tumor was positive for carbonic anhydrase IX, cytokeratin 7, cytokeratin 20, and CD10, and negative for TFE3. This emerging entity is highly correlated to tuberous sclerosis complex, which justifies a screening for the syndrome when this diagnosis is made.

Keywords: Carcinome à cellules rénales; Leiomyomatous stroma; Mutation TSC2; Métaplasie osseuse; Osseous metaplasia; Renal cell carcinoma; Sclérose tubéreuse; Stroma léiomyomateux; TSC2 gene mutation; Tuberous sclerosis.

Background: Perivascular epithelioid cell tumor (PEComa) is an uncommon tumor of mesenchymal origin. Cases of PEComa in the liver are extremely rare.

Aim: To analyze the clinicopathological features and treatment of hepatic PEComa and to evaluate the prognosis after different treatments.

Methods: Clinical and pathological data of 26 patients with hepatic PEComa were collected. All cases were analyzed by immunohistochemistry and clinical follow-up.

Results: This study included 17 females and 9 males, with a median age of 50 years. Lesions were located in the left hepatic lobe in 13 cases, in the right lobe in 11, and in the caudate lobe in 2. The median tumor diameter was 6.5 cm. Light microscopy revealed that the tumor cells were mainly composed of epithelioid cells. The cytoplasm contained heterogeneous eosinophilic granules. There were thick-walled blood vessels, around which tumor cells were radially arranged. Immunohistochemical analysis of pigment-derived and myogenic markers in PEComas revealed that 25 cases were HMB45 (+), 23 were Melan-A (+), and 22 SMA (+). TFE3 and Desmin were negative in all cases. All the fluorescence in situ hybridization samples were negative for TFE3 gene break-apart probe. Tumor tissues were collected by extended hepatic lobe resection or simple hepatic tumor resection as the main treatments. Median follow-up was 62.5 mo. None of the patients had metastasis or recurrence, and there were no deaths due to the disease.

Conclusion: Hepatic PEComa highly expresses melanin and smooth muscle markers, and generally exhibits an inert biological behavior. The prognosis after extended hepatic lobe resection and simple hepatic tumor resection is semblable.

Keywords: Hepatic tumor; Immunohistochemistry; PEComa; Perivascular epithelioid cells; Prognosis; Treatment.

Non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease worldwide and can progress to non-alcoholic steatohepatitis (NASH), which is characterized by triglyceride accumulation, inflammation, and fibrosis. No pharmacological agents are currently approved to treat these conditions, but it is clear now that modulation of lipid synthesis and autophagy are key biological mechanisms that could help reduce or prevent these liver diseases. The folliculin (FLCN) protein has been recently identified as a central regulatory node governing whole body energy homeostasis, and we hypothesized that FLCN regulates highly metabolic tissues like the liver. We thus generated a liver specific Flcn knockout mouse model to study its role in liver disease progression. Using the methionine- and choline-deficient diet to mimic liver fibrosis, we demonstrate that loss of Flcn reduced triglyceride accumulation, fibrosis, and inflammation in mice. In this aggressive liver disease setting, loss of Flcn led to activation of transcription factors TFEB and TFE3 to promote autophagy, promoting the degradation of intracellular lipid stores, ultimately resulting in reduced hepatocellular damage and inflammation. Hence, the activity of FLCN could be a promising target for small molecule drugs to treat liver fibrosis by specifically activating autophagy. Collectively, these results show an unexpected role for Flcn in fatty liver disease progression and highlight new potential treatment strategies.

Spinal cord injury (SCI) refers to a major worldwide cause of accidental death and disability. However, the complexity of the pathophysiological mechanism can result in less-effective clinical treatment. Growth differentiation factor 11 (GDF-11), an antiageing factor, was reported to affect the development of neurogenesis and exert a neuroprotective effect after cerebral ischaemic injury. The present work is aimed at investigating the influence of GDF-11 on functional recovery following SCI, in addition to the potential mechanisms involved. We employed a mouse model of spinal cord contusion injury and assessed functional outcomes via the Basso Mouse Scale and footprint analysis following SCI. Using western blot assays and immunofluorescence, we analysed the levels of pyroptosis, autophagy, necroptosis, and molecules related to the AMPK-TRPML1-calcineurin signalling pathway. The results showed that GDF-11 noticeably optimized function-related recovery, increased autophagy, inhibited pyroptosis, and alleviated necroptosis following SCI. Furthermore, the conducive influences exerted by GDF-11 were reversed with the application of 3-methyladenine (3MA), an autophagy suppressor, indicating that autophagy critically impacted the therapeutically related benefits of GDF-11 on recovery after SCI. In the mechanistic study described herein, GDF-11 stimulated autophagy improvement and subsequently inhibited pyroptosis and necroptosis, which were suggested to be mediated by TFE3; this effect resulted from the activity of TFE3 through the AMPK-TRPML1-calcineurin signalling cascade. Together, GDF-11 protects the injured spinal cord by suppressing pyroptosis and necroptosis via TFE3-mediated autophagy augmentation and is a potential agent for SCI therapy.

Alveolar soft part sarcoma (ASPS) and certain perivascular epithelioid cell neoplasms (PEComas) exhibit overlapping histopathological features, including immunohistochemical expression of TFE3, as well as TFE3 gene rearrangement. PEComas with an epithelioid morphology are known to exhibit variable immunoexpression of muscle markers. At the same time, aberrant immunoreactivity of HMB45 immunostain, which is invariably, used to substantiate a diagnosis of a PEComa, has been reported in various other tumors. Herein, we discuss two rare cases of soft tissue tumors with overlapping morphological and immunohistochemical features. Case1: A 34-year-old male underwent a biopsy for a recurrent, right-sided nasal polyp. Biopsy showed polygonal tumor cells, containing prominent nucleoli, arranged in a "nesting-type"/alveolar growth pattern. Immunohistochemically, tumor cells displayed TFE3 positivity and an aberrant positivity for HMB45. Special stain (PAS-diastase) highlighted intracytoplasmic granules and crystals. Diagnosis of ASPS was offered. Furthermore, the tumor cells displayed TFE3 gene rearrangement. Case 2: A 29-year-old female underwent an aural polypectomy. Microscopic examination revealed a tumor with a "nesting-type"/alveolar arrangement of tumor cells with vacuolated cytoplasm, arranged around thin-walled blood vessels. Immunohistochemically, tumor cells were diffusely positive for HMB45 and TFE3 and focally for SMA. A diagnosis of a PEComa was offered. This report constitutes the first documentation of aberrant HMB45 immunoreactivity in case of ASPS, and one of the first reported cases of a PEComa in the ear. It emphasizes the value of integrating clinicopathological features with immunohistochemical and molecular results in differentiating two rare, but distinct soft tissue tumors with overlapping features. An exact diagnosis of both these tumor entities has therapeutic implications.

Keywords: Alveolar soft part sarcoma; HMB45 aberrant cross-reactivity; PEComa; TFE3; TFE3 gene rearrangement.

Epithelioid hemangioendothelioma (EHE) is a rare low-grade malignant vascular tumor with indolent biology, characterized by reciprocal t(1;3)(p36.6;q25) with resultant WWTR1::CAMTA1 gene fusion in the vast majority of cases, regardless of anatomic location. Only a small subset, exhibiting well formed vasoformative features will contain YAP1::TFE3 gene fusion. Primary intranodal EHE is exquisitely rare. We report a case in a 54-year-old male with persistent left groin mass with discomfort for nine months. A CT of the abdomen and pelvis showed a minimally enlarged left inguinal lymph node measuring 2.8 cm with no other masses or lymphadenopathy. PET/CT and MRI imaging of the abdomen showed no evidence of disease elsewhere. Sections showed an epithelioid vasoformative neoplasm, centrally necrotic and involving a lymph node. The cells were arranged in anastomosing cords with intracytoplasmic lumens, resembling "signet ring cells". By immunohistochemistry, the tumor cells were positive for vimentin, CD31, CD34, ERG and CAMTA1; and negative for AE1/3, CAM 5.2, KRT7, KRT20, desmin, actin, HMB-45 and S-100. Ki-67 proliferation index was estimated at <1%. Molecular studies including next generation sequencing (NGS) revealed the presence of WWTR1::CAMTA1 gene fusion, and fluorescence in situ hybridization for CAMTA1 (1p36.23) and WWTR1 (3p25.1) showed fusion signals, diagnostic of EHE. We highlight a rare occurrence of EHE in a lymph node exhibiting morphologic mimicry with metastatic carcinoma.

Keywords: Epithelioid hemangioendothelioma; WWTR1::CAMTA1 gene fusion; intranodal; molecular genetics; primary.

Microphthalmia-associated transcription factor (MITF/MiT) family is a group of basic helix-loop-helix leucine zipper (bHLH-LZ) transcription factors including TFE3 (TFEA), TFEB, TFEC and MITF. The first renal neoplasms involving MITF family translocation were renal cell carcinomas with chromosome translocations involving ASPL-TFE3/t(X;17)(p11.23;q25) or MALAT1-TFEB/t(6;11)(p21.1;q12), and now it is known as MiT family translocation RCC in 2016 WHO classification. Translocations involving MITF family genes also are found in other tumor types, such as perivascular epithelioid cell neoplasm (PEComa), Alveolar soft part sarcoma (ASPS), epithelioid hemangioendothelioma, ossifying fibromyxoid tumor (OFMT), and clear cell tumor with melanocytic differentiation and ACTIN-MITF translocation. In this review, we summarize the features of different types of neoplasms with MITF family translocations.

Metabolic homeostasis requires dynamic catabolic and anabolic processes. Autophagy, an intracellular lysosomal degradative pathway, can rewire cellular metabolism linking catabolic to anabolic processes and thus sustain homeostasis. This is especially relevant in the liver, a key metabolic organ that governs body energy metabolism. Autophagy's role in hepatic energy regulation has just begun to emerge and autophagy seems to have a much broader impact than what has been appreciated in the field. Though classically known for selective or bulk degradation of cellular components or energy-dense macromolecules, emerging evidence indicates autophagy selectively regulates various signaling proteins to directly impact the expression levels of metabolic enzymes or their upstream regulators. Hence, we review three specific mechanisms by which autophagy can regulate metabolism: A) nutrient regeneration, B) quality control of organelles, and C) signaling protein regulation. The plasticity of the autophagic function is unraveling a new therapeutic approach. Thus, we will also discuss the potential translation of promising preclinical data on autophagy modulation into therapeutic strategies that can be used in the clinic to treat common metabolic disorders.

Keywords: AIM, Atf8 interacting motif; ATGL, adipose triglyceride lipase; ATL3, Atlastin GTPase 3; ATM, ATM serine/threonine kinase; Autophagy; BA, bile acid; BCL2L13, BCL2 like 13; BNIP3, BCL2 interacting protein 3; BNIP3L, BCL2 interacting protein 3 like; CAR, constitutive androstane receptor; CCPG1, cell cycle progression 1; CLN3, lysosomal/endosomal transmembrane protein; CMA, chaperonin mediated autophagy; CREB, cAMP response element binding protein; CRY1, cryptochrome 1; CYP27A1, sterol 27-hydroxylase; CYP7A1, cholesterol 7α-hydroxylase; Cryptochrome 1; DFCP1, double FYVE-containing protein 1; FAM134B, family with sequence similarity 134, member B; FFA, free fatty acid; FOXO1, Forkhead box O1; FUNDC1, FUN14 domain containing 1; FXR, farnesoid X receptor; Farnesoid X receptor; GABARAPL1, GABA type A receptor associated protein like 1; GIM, GABARAP-interacting motif; LAAT-1, lysosomal amino acid transporter 1 homologue; LALP70, lysosomal apyrase-like protein of 70 kDa; LAMP1, lysosomal-associated membrane protein-1; LAMP2, lysosomal-associated membrane protein-2; LD, lipid droplet; LIMP1, lysosomal integral membrane protein-1; LIMP3, lysosomal integral membrane protein-3; LIR, LC3 interacting region; LXRa, liver X receptor a; LYAAT-1, lysosomal amino acid transporter 1; Liver metabolism; Lysosome; MCOLN1, mucolipin 1; MFSD1, major facilitator superfamily domain containing 1; NAFLD, non-alcoholic fatty liver disease; NBR1, BRCA1 gene 1 protein; NCoR1, nuclear receptor co-repressor 1; NDP52, calcium-binding and coiled-coil domain-containing protein 2; NPC-1, Niemann-Pick disease, type C1; Nutrient regeneration; OPTN, optineurin; PEX5, peroxisomal biogenesis factor 5; PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase; PINK1, phosphatase and tensin homolog (PTEN)-induced kinase 1; PKA, protein kinase A; PKB, protein kinase B; PLIN2, perilipin 2; PLIN3, perilipin 3; PP2A, protein phosphatase 2a; PPARα, peroxisomal proliferator-activated receptor-alpha; PQLC2, PQ-loop protein; PXR, pregnane X receptor; Quality control; RETREG1, reticulophagy regulator 1; ROS, reactive oxygen species; RTN3, reticulon 3; RTNL3, a long isoform of RTN3; S1PR2, sphingosine-1-phosphate receptor 2; S6K, P70-S6 kinase; S6RP, S6 ribosomal protein; SCARB2, scavenger receptor class B member 2; SEC62, SEC62 homolog, preprotein translocation factor; SIRT1, sirtuin 1; SLC36A1, solute carrier family 36 member 1; SLC38A7, solute carrier family 38 member 7; SLC38A9, sodium-coupled neutral amino acid transporter 9; SNAT7, sodium-coupled neutral amino acid transporter 7; SPIN, spindling; SQSTM1, sequestosome 1; STBD1, starch-binding domain-containing protein 1; Signaling proteins; TBK1, serine/threonine-protein kinase; TEX264, testis expressed 264, ER-phagy receptor; TFEB/TFE3, transcription factor EB; TGR5, takeda G protein receptor 5; TRAC-1, thyroid-hormone-and retinoic acid-receptor associated co-repressor 1; TRPML1, transient receptor potential mucolipin 1; ULK1, Unc-51 like autophagy activating kinase 1; UPR, unfolded protein response; V-ATPase, vacuolar-ATPase; VDR, vitamin D3 receptor; VLDL, very-low-density lipoprotein; WIPI1, WD repeat domain phosphoinositide-interacting protein 1; mTORC1, mammalian target of rapamycin complex 1.

Translocation-associated renal cell carcinoma (tRCC) is a rare, aggressive malignancy that primarily affects children and young adults. There is no clear consensus on the most effective treatment for tRCC and there are no biomarkers of response to treatments in these patients. We present a case of a 23 year-old female with metastatic tRCC to the lungs who was started on treatment with nivolumab and ipilimumab. She had a complete radiographic response to treatment and has been progression-free for over 18 months. Immunofluorescence imaging performed on the baseline primary tumor sample showed significant intratumoral immune infiltration. Importantly, these cells are present in niches characterized by TCF1+ CD8+ T cells. Histopathologic investigation showed the presence of lymphocytes in the fibrovascular septae and foci of lymphovascular invasion. Furthermore, lymphovascular invasion and intratumor niches with TCF1+ CD8+ T cells may predict a favorable response to treatment with nivolumab and ipilimumab. These findings have significant clinical relevance given that immune checkpoint inhibitors are approved for several malignancies and predictive biomarkers for response to treatment are lacking. Importantly, the identification of these TCF1+ CD8+ T cells may guide treatment for patients with tRCC, which is a rare malignancy without a consensus first-line treatment option.

Keywords: TCF1+ CD8+ T cells; combination immune checkpoint therapy; exceptional responder; intratumoral immune niche; rare malignancy; translocation-associated RCC.