Amino acids and their roles in tumor immunotherapy of breast cancer.

Breast cancer is the most commonly diagnosed cancer among women. The primary treatment options include surgery, radiotherapy, chemotherapy, targeted therapy and hormone therapy. The effectiveness of breast cancer therapy varies depending on the stage and aggressiveness of the cancer, as well as individual factors. Advances in early detection and improved treatments have significantly increased survival rates for breast cancer patients. Nevertheless, specific subtypes of breast cancer, particularly triple-negative breast cancer, still lack effective treatment strategies. Thus, novel and effective therapeutic targets for breast cancer need to be explored. As substrates of protein synthesis, amino acids are important sources of energy and nutrition, only secondly to glucose. The rich supply of amino acids enables the tumor to maintain its proliferative competence through participation in energy generation, nucleoside synthesis and maintenance of cellular redox balance. Amino acids also play an important role in immune-suppressive microenvironment formation. Thus, the biological effects of amino acids may change unexpectedly in tumor-specific or oncogene-dependent manners. In recent years, there has been significant progress in the study of amino acid metabolism, particularly in their potential application as therapeutic targets in breast cancer. In this review, we provide an update on amino acid metabolism and discuss the therapeutic implications of amino acids in breast cancer.

A regulatory role of the medial septum in the chloroquine-induced acute itch through local GABAergic system and GABAergic pathway to the anterior cingulate cortex.

Itch, a common somatic sensation, serves as a crucial protective system. Recent studies have unraveled the neural mechanisms of itch at peripheral, spinal cord as well as cerebral levels. However, a comprehensive understanding of the central mechanism governing itch transmission and regulation remains elusive. Here, we report the role of the medial septum (MS), an integral component of the basal forebrain, in modulating the acute itch processing. The increases in c-Fos+ neurons and calcium signals within the MS during acute itch processing were observed. Pharmacogenetic activation manipulation of global MS neurons suppressed the scratching behaviors induced by chloroquine or compound 48/80. Microinjection of GABA into the MS or pharmacogenetic inhibition of non-GABAergic neurons markedly suppressed chloroquine-induced scratching behaviors. Pharmacogenetic activation of the MS-ACC GABAergic pathway attenuated chloroquine-induced acute itch. Hence, our findings reveal that MS has a regulatory role in the chloroquine-induced acute itch through local increased GABA to inhibit non-GABAergic neurons and the activation of MS-ACC GABAergic pathway.

Analgesic Effect of Exercise on Neuropathic Pain via Regulating the Complement Component 3 of Reactive Astrocytes.

BACKGROUND: Exercise has been proven to be an efficient intervention in attenuating neuropathic pain. However, the underlying mechanisms that drive exercise analgesia remain unknown. In this study, we aimed to examine the role of complement component 3 (C3) in neuropathic pain and whether antinociceptive effects are produced by exercise via regulating C3 in mice. METHODS: In this study, using a spared nerve injury (SNI)-induced neuropathic pain mice model, C57BL/6J mice were divided into 3 groups: Sham mice, SNI mice, and SNI + Exercise (Ex) mice with 30-minute low-intensity aerobic treadmill running (10 m/min, no inclination). Paw withdrawal threshold; thermal withdrawal latency; and glial fibrillary acidic protein, C3, tumor necrosis factor-α, and interlukin-1ß expression in the spinal cord were monitored. C3 knockout (KO) mice were further used to verify the role of C3 in neuropathic pain. RESULTS: von Frey test, acetone test, and CatWalk gait analysis revealed that treadmill exercise for 4 weeks reversed pain behaviors. In addition, exercise reduced astrocyte reactivity (SNI mean = 14.5, 95% confidence interval [CI], 12.7-16.3; SNI + Ex mean = 10.3, 95% CI, 8.77-11.9, P = .0003 SNI + Ex versus SNI) and inflammatory responses in the spinal cord after SNI. Moreover, it suppressed the SNI-induced upregulation of C3 expression in the spinal cord (SNI mean = 5.46, 95% CI, 3.39-7.53; SNI + Ex mean = 2.41, 95% CI, 1.42-3.41, P = .0054 SNI + Ex versus SNI in Western blot). C3 deficiency reduced SNI-induced pain and spinal astrocyte reactivity (wild type mean = 7.96, 95% CI, 6.80-9.13; C3 KO mean = 5.98, 95% CI, 5.14-6.82, P = .0052 C3 KO versus wild type). Intrathecal injection of recombinant C3 (rC3) was sufficient to produce mechanical (rC3-Ex mean = 0.77, 95% CI, 0.15-1.39; rC3 mean = 0.18, 95% CI, -0.04 to 0.41, P = .0168 rC3-Ex versus rC3) and cold (rC3-Ex mean = 1.08, 95% CI, 0.40-1.77; rC3 mean = 3.46, 95% CI, 1.45-5.47, P = .0025 rC3-Ex versus rC3) allodynia in mice. Importantly, exercise training relieved C3-induced mechanical and cold allodynia, and the analgesic effect of exercise was attenuated by a subeffective dose of intrathecal injection of C3. CONCLUSIONS: Overall, these results suggest that exercise suppresses neuropathic pain by regulating astroglial C3 expression and function, thereby providing a rationale for the analgesic effect of exercise as an acceptable alternative approach for treating neuropathic pain.

Neutrophils in triple-negative breast cancer: an underestimated player with increasingly recognized importance.

Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer, with limited therapeutic options readily available. Immunotherapy such as immune checkpoint inhibition has been investigated in TNBC but still encounters low overall response. Neutrophils, the most abundant leukocytes in the body, are increasingly recognized as an active cancer-modulating entity. In the bloodstream, neutrophils escort circulating tumor cells to promote their survival and stimulate their proliferation and metastasis. In the tumor microenvironment, neutrophils modulate the immune milieu through polarization between the anti-tumor and the pro-tumor phenotypes. Through a comprehensive review of recently published literature, it is evident that neutrophils are an important player in TNBC immunobiology and can be used as an important prognostic marker of TNBC. Particularly, in their pro-tumor form, neutrophils facilitate TNBC metastasis through formation of neutrophil extracellular traps and the pre-metastatic niche. These findings will help advance the potential utilization of neutrophils as a therapeutic target in TNBC.

Natural mineral-derived Fe/Mn-BC as efficient peroxydisulfate activator for 2,4-dichlorophenol removal from wastewater: Performance and sustainable catalytic mechanism.

Iron and manganese oxides/biochar composite materials (Fe/Mn-BC) are promising catalysts in the field of advanced oxidation. High purity chemical reagents are popular precursors for preparing Fe/Mn-BC, while the potential of low-cost natural minerals as precursors has been neglected. In this study, high-efficiency Fe/Mn-BC was synthesized by one-step pyrolysis method using hematite, phosphoromanganese, and bagasse. The synthesized Fe/Mn-BC removed 83.7% 2, 4-dichlorophenol (2, 4-DCP) within 30 min, about 8.8 and 10.6 times better than biochar (BC) and Fe/Mn complex, respectively. The removal of 2, 4-DCP in the Fe/Mn-BC + peroxydisulfate (PDS) system was influenced by catalyst dosage, PDS concentration, initial pH, organic acids, and chromium. Sulfate radical (SO4•-) and hydroxyl radicals (•OH) generated by Fe/Mn-BC-activated PDS have similar contribution to the degradation of 2,4-DCP. A possible removal mechanism of 2, 4-DCP in the Fe/Mn-BC + PDS system was proposed based on Electron Spin Resonance spectroscopy, free radical quenching experiments, X-ray photoelectron spectroscopy, X-ray diffraction, and electrochemical measurement. Fe0 and Fe(II) in Fe/Mn-BC play significant role in catalytic degradation of 2, 4-DCP at the early stage of the reaction (within 0-5 min). Then, the interaction between Mn and BC or structural Mn and structural Fe gradually became dominant in the later stage. Similarly, the electron transfer promoted by biochar also played an important role in this catalysis. This discovery provided a new strategy for developing iron and manganese oxides/biochar composite materials to activate PDS for the elimination of refractory organic pollutants.

Lovastatin enhances chemosensitivity of paclitaxel-resistant prostate cancer cells through inhibition of CYP2C8.

Chemotherapy is the mainstay of treatment for prostate cancer, with paclitaxel being commonly used for hormone-resistant prostate cancer. However, drug resistance often develops and leads to treatment failure in a variety of prostate cancer patients. Therefore, it is necessary to enhance the sensitivity of prostate cancer to chemotherapy. Lovastatin (LV) is a natural compound extracted from Monascus-fermented foods and is an inhibitor of HMG-CoA reductase (HMGCR), which has been approved by the FDA for hyperlipidemia treatment. We have previously found that LV could inhibit the proliferation of refractory cancer cells. Up to now, the effect of LV on chemosensitization and the mechanisms involved have not been evaluated in drug-resistant prostate cancer. In this study, we used prostate cancer cell line PC3 and its paclitaxel-resistant counterpart PC3-TxR as the cell model. Alamar Blue cell viability assay showed that LV and paclitaxel each conferred concentration-dependent inhibition of PC3-TxR cells. When paclitaxel was combined with LV, the proliferation of PC3-TxR cells was synergistically inhibited, as demonstrated by combination index <1. Moreover, colony formation decreased while apoptosis increased in paclitaxel plus LV group compared with paclitaxel alone group. Quantitative RT-PCR showed that the combination of paclitaxel and LV could significantly reduce the expression of CYP2C8, an important drug-metabolizing enzyme. Bioinformatics analysis from the TCGA database showed that CYP2C8 expression was negatively correlated with progression-free survival (PFS) in prostate cancer patients. Our results suggest that LV might increase the sensitivity of resistant prostate cancer cells to paclitaxel through inhibition of CYP2C8 and could be utilized as a chemosensitizer for paclitaxel-resistant prostate cancer cells.

A functional promoter from the archaeon Halobacterium salinarum is also transcriptionally active in E. coli.

BACKGROUND: Archaea form a third domain of life that is distinct from Bacteria and Eukarya. So far, many scholars have elucidated considerable details about the typical promoter architectures of the three domains of life. However, a functional promoter from the archaeon Halobacterium salinarum has never been studied in Escherichia coli. RESULTS: This paper found that the promoter of Halobacterium salinarum showed a promoter function in Escherichia coli. This Escherichia coli promoter structure contains - 10 box, -10 box extension and - 29 elements, however, no -35 box. The - 29 element is exercised by the TATA box in archaea. And we isolated the RM10 fragment that possessed the fusion characteristics of bacteria and archaea, which was overlapped with functionality of TATA box and - 29 elements. CONCLUSIONS: The - 29 element reflects the evolutionary relationship between the archaeal promoter and the bacterial promoter. The result possibly indicated that there may be a certain internal connection between archaea and bacteria. We hypothesized that it provided a new viewpoint of the evolutionary relationship of archaea and other organisms.

One-step synthesis of natural montmorillonite/hematite composites with enhanced persulfate catalytic activity for sulfamethoxazole degradation: Efficiency, kinetics, and mechanism.

Along with rapid development of sulfate radicals-based advanced oxidation process, efficient, alternatively eco-friendly and cost-effective catalyst is of uppermost priority. However, expensive chemicals are used as source of metal in most of these catalysts, and lose sight of the abundant natural mineral resources on immediate surroundings. In this work, montmorillonite and hematite, two of abundantly natural minerals were utilized to prepare a persulfate catalyst (TMH@M) for sulfamethoxazole (SMX) degradation. The results indicated more than 91% of SMX was removed within 60 min in TMH@M/PS system. The degradation efficiency of SMX of TMH@M/PS combined system was impacted by SMX concentration, PS dosage and natural organic matters, and can remain stable in a certain concentration of HA/chelating agent and a wide pH range (3.01-9.06). Radical scavenging and EPR tests demonstrated 1O2, OH, and SO4- were major reactive oxygen species in the TMH@M/PS system, while the latter seems more important for degradation of SMX. The results of SEM-EDS, XRD and XPS conformed that low valence iron species (Fe0, Fe2+ and Fe3O4) on TMH@M surface are the main driving force behind PS activation to generate reactive species. Furthermore, the iron species on TMH@M surface were transformed during reaction, that in favor of mitigating metal leaching. This work presented a method based on ubiquitous natural minerals to prepare catalyst with excellent PS activate performance for organic wastewater treatment implying a new strategy in minerals utilization deeply and a promisingly alternative process for organic wastewater treatment based on mineral materials.

Elevated IL-23 in skin promotes IL-23 derived Th17 responses in leprosy patients.

Leprosy is an infectious disease caused by non-cultivable bacteria Mycobacterium leprae. Th17 cells play vital roles during pathogenesis of leprosy reactions and IL-23 is involved in Th17 cell differentiation. Although previous studies have reported the participation of IL-23 in leprosy patients in peripheral blood, the role of this cytokine in skin has not yet been described for the disease. In this study, we first evaluated IL-23 expression in the skin of patients with leprosy. Data showed that in keratinocytes, endothelial cells, and macrophages, IL-23 expression was markedly higher in patients compared to that in the normal skin controls. Also, leprosy patients presented higher percentage of IL-17A-producing IL-23R + CD4 T cells than healthy donors. IL-23R blocking induced markedly downregulated IL-17A secretion in leprosy patients but not in healthy donors. Furthermore, TGF-ß expression was significantly elevated after IL-23R blocking. Overall, this study establishes that Th17 cells produce IL-17A in an IL-23 dependent manner in the skin of leprosy patients and provides more focused treatment strategies for Mycobacterium leprae.

Mangiferin prevents myocardial infarction-induced apoptosis and heart failure in mice by activating the Sirt1/FoxO3a pathway.

Myocardial infarction (MI) commonly leads to cardiomyocyte apoptosis and heart failure. Mangiferin is a natural glucosylxanthone extracted from mango fruits and leaves, which has anti-apoptotic and anti-inflammatory properties in experimental cardiovascular diseases. In the present study, we investigated the role and detailed mechanism of mangiferin in MI. We used ligation of the left anterior descending coronary artery to establish an MI model in vivo, and cardiomyocyte-specific Sirt1 knockout mice were used to identify the mechanism of mangiferin. For in vitro studies, oxygen and glucose deprivation (OGD) was used to mimic ischaemia in H9c2 cardiomyocytes. In mice, mangiferin treatment increased Sirt1 expression after MI, significantly reduced the infarct area, and prevented MI-induced apoptosis and heart failure. Mangiferin reduced OGD-induced cellular apoptosis in H9c2 cells. Meanwhile, Sirt1 knockout/silencing abolished the protective effects of mangiferin. Further studies revealed that mangiferin increased FoxO3a deacetylation by up-regulating Sirt1, thus preventing apoptosis, and adenovirus-mediated constitutive acetylation of FoxO3a restricted the anti-apoptotic effects of mangiferin in vivo and in vitro. Our results indicate that mangiferin prevents cardiomyocyte apoptosis and the subsequent heart failure by activating the Sirt1/FoxO3a pathway in MI, and suggest that mangiferin may have an interesting potential in following studies towards clinical evaluation.

Production of highly sensitive monoclonal antibody and development of lateral flow assays for phallotoxin detection in urine.

Phallotoxins, toxic cyclopeptides found in wild poisonous mushrooms, are predominant causes of fatal food poisoning. For the early and rapid diagnosis mushroom toxin poisoning, a highly sensitive and robust monoclonal antibody (mAb) against phallotoxins was produced for the first time. The half-maximum inhibition concentration (IC50) values of the mAb-based indirect competitive ELISAs for phallacidin (PCD) and phalloidin (PHD) detection were 0.31 ng mL-1 and 0.35 ng mL-1, respectively. In response to the demand for rapid screening of the type of poisoning and accurate determination of the severity of poisoning, colloidal gold nanoparticle (GNP) and time-resolved fluorescent nanosphere (TRFN) based lateral flow assays (LFA) were developed. The GNP-LFA has a visual cut-off value of 3.0 ng mL-1 for phallotoxins in human urine sample. The TRFN-LFA provides a quantitative readout signal with detection limit of 0.1 ng mL-1 in human urine sample. In this study, urine samples without pretreatment were used directly for the LFA strip tests, and both two LFAs were able to accomplish analysis within 10 min. The results demonstrated that LFAs based on the newly produced, highly sensitive, and robust mAb were able to be used for both rapid qualitative screening of the type of poisoning and accurate quantitative determination of the severity of poisoning after accidental ingestion by patients of toxic mushrooms.

Initiation of translation in bacteria by a structured eukaryotic IRES RNA.

The central dogma of gene expression (DNA to RNA to protein) is universal, but in different domains of life there are fundamental mechanistic differences within this pathway. For example, the canonical molecular signals used to initiate protein synthesis in bacteria and eukaryotes are mutually exclusive. However, the core structures and conformational dynamics of ribosomes that are responsible for the translation steps that take place after initiation are ancient and conserved across the domains of life. We wanted to explore whether an undiscovered RNA-based signal might be able to use these conserved features, bypassing mechanisms specific to each domain of life, and initiate protein synthesis in both bacteria and eukaryotes. Although structured internal ribosome entry site (IRES) RNAs can manipulate ribosomes to initiate translation in eukaryotic cells, an analogous RNA structure-based mechanism has not been observed in bacteria. Here we report our discovery that a eukaryotic viral IRES can initiate translation in live bacteria. We solved the crystal structure of this IRES bound to a bacterial ribosome to 3.8 Å resolution, revealing that despite differences between bacterial and eukaryotic ribosomes this IRES binds directly to both and occupies the space normally used by transfer RNAs. Initiation in both bacteria and eukaryotes depends on the structure of the IRES RNA, but in bacteria this RNA uses a different mechanism that includes a form of ribosome repositioning after initial recruitment. This IRES RNA bridges billions of years of evolutionary divergence and provides an example of an RNA structure-based translation initiation signal capable of operating in two domains of life.

Internal Migration and Leprosy in Shanghai from 2000 to 2019: an Epidemiological Study of New Cases.

Leprosy is a chronic infectious disease caused by Mycobacterium leprae. Massive internal migration from rural to urban areas poses new challenges for leprosy control in Shanghai, China. This retrospective epidemiological study examined new cases of leprosy diagnosed in Shanghai from 2000 to 2019, with emphasis on internal migration cases. There were 145 cases of leprosy in the study period; the majority of cases (89.0%) were internal migrants. Migrant cases had a mean of 25.4 months lag time from onset of symptoms to diagnosis, which was significantly longer than that of resident cases (mean 10.8 months, p < 0.001). Greater lag time from the first visit to diagnosis was observed in migrant cases (mean 23.2 months) compared with resident cases (mean 9.4 months, p < 0.001). A large majority of cases (91.0%) had been misdiagnosed. Internal migrant cases were responsible for most incidences of leprosy in Shanghai. They often did not receive timely diagnosis and treatment, which may have an adverse impact on the prevention of epidemic leprosy.

Clinical profiles of silent corticotroph adenomas compared with silent gonadotroph adenomas after adopting the 2017 WHO pituitary classification system.

PURPOSE: Silent corticotroph adenomas (SCAs) can be redefined according to the 2017 World Health Organization pituitary classification system with the introduction of T­PIT, a transcription factor. We studied the clinical features of these redefined SCAs. METHODS: We compared 112 patients with SCAs and 198 patients with silent gonadotroph adenomas (SGAs) who underwent surgery from January 2019 to May 2020. RESULTS: The prevalence of SCAs increased from 21.3 to 30.2% under the new classification rules. T-PIT-positive, adrenocorticotropic hormone-negative SCAs and T-PIT-positive, adrenocorticotropic hormone-positive SCAs exhibited similar clinical features. SCAs exhibited significant female preponderance (90.2% vs. 29.8%, P < 0.0001); more frequent invasion (36.6% vs. 7.6%, P < 0.0001), especially multiple-site invasion (P < 0.0001); and marked cystic changes on imaging compared with SGAs (54.5% vs. 19.2%, P < 0.0001). SCAs had a softer tumor consistency (89.2% vs. 61.1%, P < 0.0001). Gross total resection was achieved in 66.1% of SCAs and 66.2% of SGAs (P > 0.9999). The overall recurrence/progression rates of SCAs and SGAs were 9.8% and 6.6% at 14.1 and 13.5 months of follow-up, respectively (P = 0.3765). The proportion of patients with more than two recurrences requiring multiple surgeries and radiation was similar between SCAs and SGAs (7.1% vs. 3.0%, P = 0.1514). However, multiple recurrences of SCAs affected younger patients than SGAs (39.0 vs. 53.5 years, P = 0.0433). CONCLUSIONS: The prevalence of SCAs increased with the introduction of T-PIT. SCAs and SGAs exhibited comparable size and recurrence/progression rates, but SCAs showed increased invasion and more marked cystic change. Aggressive SCAs tended to affect younger patients. Close long-term monitoring for SCA recurrence/progression is required.

Suprasellar pituitary adenomas: a 10-year experience in a single tertiary medical center and a literature review.

BACKGROUND: Suprasellar pituitary adenomas (SPAs) are a special type of pituitary adenoma. Although dozens of SPA cases have been reported, the exact definition and the characteristics of SPA have not been exhaustively discussed before. METHODS: In a retrospective electronic medical records review, 13 patients with SPA were identified in our hospital between January 2010 and December 2019. A literature review was performed by searching the online database PubMed, and 39 cases conformed to the criteria based on the previous literature. Data regarding clinical symptoms, imaging manifestations, surgical information and follow-ups were analyzed. RESULTS: The mean age at diagnosis of 52 patients with SPA was 36.73 years, and most of the patients were female (61.5%). The most common hormone-secreting subtypes of SPA were nonfunctioning (36.5%) and ACTH-secreting (34.6%) SPA. Macroadenomas (68.9%) were more common than microadenomas (31.1%). The origins of the SPAs included the intrasellar pituitary gland (type I), the subdiaphragmatic (type IIa) and supradiaphragmatic (type IIb) part of the pituitary stalk, and the suprasellar peri-infundibular region (type III). The most common anatomic subtype of SPA was type III, and type IIb was also common. The most common presentations of SPA were visual symptoms, especially for type III SPA. In addition, 64.7% and 73.1% of type IIb and III SPAs, respectively, were suspected to be of suprasellar origin based on presurgical imaging examination. Patients with tumors of suspected suprasellar origin were more likely to receive transcranial surgery (TCS) initially than those with tumors of suspected intrasellar origin (70.6% vs. 22.2%, p = 0.0013). The intact rate for the pituitary stalk after surgery for type II SPA was lower than that for type I and III SPA (52.6% vs. 92.6%, p = 0.0036). More patients with type II SPA experienced postoperative central diabetes insipidus (CDI) than those with type I and III SPA (57.9% vs. 11.1%, p = 0.0011). There was no significant difference in the incidence of postoperative CDI between transsphenoidal surgery (TSS) and TCS (p = 0.1304). Nine patients in our hospital received extended endoscopic TSS; only one experienced tumor recurrence, and no severe complications occurred after surgery. CONCLUSIONS: SPAs could be defined as pituitary adenomas completely or partially located in the suprasellar region. There were both similarities and differences among the different anatomic subtypes of SPA. For patients who were suspected of having SPAs, visual field tests, pituitary hormone evaluation and MRI were necessary. Because imaging examination is not a reliable method, surgery is the only way to confirm the tumor origin. Extended endoscopic TSS might be a safe and efficient approach to remove these tumors, but more studies are needed to verify this conclusion. For type II SPA, the pituitary stalk should be carefully protected during surgery, and postoperative CDI should be monitored.

Cosecreting TSH/GH pituitary adenomas-an 8-year experience in a single tertiary center.

PURPOSE: Thyrotropin-secreting pituitary adenoma is a rare disorder and was recently classified as an aggressive tumor in the World Health Organization guidelines. The number of available studies on cosecreting thyrotropin/growth hormone pituitary adenoma is especially limited. METHODS: A single-center retrospective analysis of patients with thyrotropin/growth hormone pituitary adenoma was performed at Peking Union Medical College Hospital, one of the largest pituitary care centers in China, from January 2012 to January 2020. Additionally, data about cosecreting thyrotropin/growth hormone pituitary adenoma were collected and analyzed. The diagnosis, therapy and follow-up were all compared to that of solo-secreting thyrotropin pituitary macroadenoma. RESULTS: Twelve patients (10.81%) were identified with thyrotropin/growth hormone pituitary adenoma at Peking Union Medical College Hospital within 8 years, all of which were classified as macroadenoma. Compared with solo-secreting thyrotropin pituitary macroadenoma, thyrotropin/growth hormone pituitary adenoma presented with a higher proportion of cavernous sinus invasion (50%) and had a larger maximum tumor diameter. The patients had a lower surgical complete remission rate and a worse prognosis. Interestingly, they revealed a striking phenomenon of "solo part remission". CONCLUSIONS: Thyrotropin/growth hormone pituitary adenoma is rare. Some patients do not present with the typical manifestations; however, the possibility of a cosecretion tumor should not be excluded. A preoperative comprehensive evaluation of anterior pituitary hormones is necessary. Thyrotropin/growth hormone pituitary adenoma revealed a high tendency of invasion, and the prognosis of patients with thyrotropin/growth hormone pituitary adenoma was poor. If necessary, timely postoperative drug administration or radiotherapy should be carried out.

Ectopic pituitary adenomas: clinical features, diagnostic challenges and management.

PURPOSE: Ectopic pituitary adenomas (EPAs) are extremely rare pituitary adenomas located outside the sella turcica without any connection with intrasellar components. This study aims to review all the reported cases to date and describe the clinical characteristics of EPAs. METHODS: In a retrospective chart review, 14 patients were identified with EPAs in our hospital. A literature review was performed, and 166 cases in the literature met the criteria. Clinical data were analyzed. RESULTS: Of 180 patients with EPAs, the mean age at diagnosis was 45.4 years, and 66.5% of the patients were females. EPAs were mainly located in the sphenoid sinus (34.4%) and suprasellar region (25.6%), followed by the clivus (15.6%), cavernous sinus (13.3%) and nasopharynx (5.6%). Adrenocorticotropic hormone (ACTH)-secreting (38.9%) and nonfunctioning (27.2%) adenomas were predominant. Patients with suprasellar EPAs were more likely to present menstrual disorders and visual changes, while patients with clival EPAs were more likely to suffer from headaches. EPAs in the cavernous sinus and suprasellar space were more likely to be initially misdiagnosed as a suspicious intrasellar mass on imaging examination. The complete tumor resection rates for EPAs in the sphenoid sinus, suprasellar region, clivus, cavernous sinus and nasopharynx were 72.3%, 88.6%, 45.0%, 73.3% and 88.9%, respectively. CONCLUSIONS: EPA clinical characteristics varied across different tumor locations and hormone-secreting types. In addition to comprehensive hormone evaluation and careful review of imaging data, nuclear medicine and surgical biopsy should also be considered when facing differential difficulty. EPA management should be individualized.

Long-term follow-up for ectopic ACTH-secreting pituitary adenoma in a single tertiary medical center and a literature review.

BACKGROUND: Ectopic ACTH-secreting pituitary adenoma (EAPA) are a rare cause of Cushing's disease. Due to the lack of consensus and experience in terms of the diagnosis and treatment of EAPAs, preoperative identification and optimal treatment remain challenging. PURPOSE: To investigate the characteristics of EAPAs and offer some proposals for the diagnosis and management of this uncommon disease, the EAPA patients admitted to our center and all of the EAPA cases reported in the literature were reviewed. METHODS: In a retrospective electronic medical chart review, 6 patients (0.39%) with EAPAs were identified from 1536 consecutive patients who were admitted to our hospital with a diagnosis of Cushing's syndrome between January 2000 and August 2019. A literature review was performed on the online databases PubMed and EMBASE, and 52 cases conformed to the criteria. The data regarding biochemical tests, imaging examinations and follow-ups were analyzed. RESULTS: The mean age of patients with EAPAs was 37.7 years old, and an obvious female predominance (3.5: 1) was demonstrated. The most common location of EAPAs was the cavernous sinus (34.5%), followed by the sphenoid sinus (31.0%) and the suprasellar region (20.7%). No significant differences in the biochemical test results were found among tumors in different locations. Except for sex, no risk factors related to remission were found. Although no significant differences among different locations were found, the tumors in the cavernous sinus had a relatively higher rate of invisibility in terms of imaging and a higher non-remission rate than tumors in other locations. CONCLUSIONS: In patients with negative intrasellar findings, the uncommon disease of EAPA should be considered. Due to the endocrine similarity between intrasellar pituitary corticotrophin adenoma and EAPA, the preoperative identification of EAPA depends on a careful review of the imaging examinations. Locations such as the cavernous sinus, sphenoid sinus and suprasellar region should be considered first. Tumor resection is recommended when the diagnosis is confirmed.

Spinal IL-33/ST2 signaling mediates chronic itch in mice through the astrocytic JAK2-STAT3 cascade.

Interleukin-33 (IL-33) and its receptor ST2 contribute to spinal glial activation and chronic pain. A recent study showed that peripheral IL-33 plays a pivotal role in the pathogenesis of chronic itch induced by poison ivy. However, how IL-33/ST2 signaling in the spinal cord potentially mediates chronic itch remains elusive. Here, we determined that St2-/- substantially reduced scratching behaviors in 2,4-dinitrofluorobenzene (DNFB)-induced allergic contact dermatitis (ACD) as well as acetone and diethylether followed by water-induced dry skin in mice. Intrathecal administration of the neutralizing anti-ST2 or anti-IL-33 antibody remarkably decreased the scratching response in DNFB-induced ACD mice. Expression of spinal IL-33 and ST2 significantly increased in ACD mice, as evidenced by increased mRNA and protein levels. Immunofluorescence and in situ hybridization demonstrated that increased expression of spinal IL-33 was predominant in oligodendrocytes and astrocytes, whereas ST2 was mainly expressed in astrocytes. Further studies showed that in ACD mice, the activation of astrocytes and increased phosphorylation of signal transducer and activator of transcription 3 (STAT3) were markedly attenuated by St2-/- . Intrathecal injection of Janus Kinase 2 Inhibitor AG490 significantly alleviated scratching behaviors in ACD mice. rIL-33 pretreatment exacerbated gastrin-releasing peptide (GRP)-evoked scratching behaviors. This increased gastrin-releasing peptide receptor (GRPR) expression was abolished by St2-/- . Tnf-α upregulation was suppressed by St2-/- . Our results indicate that the spinal IL-33/ST2 signaling pathway contributes to chronic itch via astrocytic JAK2-STAT3 cascade activation, promoting TNF-α release to regulate the GRP/GRPR signaling-related itch response. Thus, these findings provide a potential therapeutic option for treating chronic pruritus.

Identifying occult maternal malignancies from 1.93 million pregnant women undergoing noninvasive prenatal screening tests.

PURPOSE: Multiple chromosomal aneuploidies may be associated with maternal malignancies and can cause failure of noninvasive prenatal screening (NIPS) tests. However, multiple chromosomal aneuploidies show poor specificity and selectivity for diagnosing maternal malignancies. METHODS: This multicenter retrospective analysis evaluated 639 pregnant women who tested positive for multiple chromosomal aneuploidies on initial NIPS test between January 2016 and December 2017. Women were assessed using genome profiling of copy-number variations, which was translated to cancer risk using a novel bioinformatics algorithm called the cancer detection pipeline (CDP). Sensitivity, specificity, and positive predictive value (PPV) of diagnosing maternal malignancies were compared for multiple chromosomal aneuploidies, the CDP model, and the combination of CDP and plasma tumor markers. RESULTS: Of the 639 subjects, 41 maternal malignant cancer cases were diagnosed. Multiple chromosomal aneuploidies predicted maternal malignancies with a PPV of 7.6%. Application of the CDP algorithm to women with multiple chromosomal aneuploidies allowed 34 of the 41 (83%) cancer cases to be identified, while excluding 422 of 501 (84.2%) of the false positive cases. Combining the CDP with plasma tumor marker testing gave PPV of 75.0%. CONCLUSION: The CDP algorithm can diagnose occult maternal malignancies with a reasonable PPV in multiple chromosomal aneuploidies-positive pregnant women in NIPS tests. This performance can be further improved by incorporating findings for plasma tumor markers.