Comparison of PD-L1, VISTA, LAG-3, and GAL-3 Expressions and Their Relationships to Mismatch Repair Protein and p53 Expression in 529 Cases of Endometrial Carcinoma.

The aim of this study is to evaluate the expressions of programmed death-ligand 1 (PD-L1), V-domain Ig suppressor of T-cell activation (VISTA), lymphocyte activation gene-3 (LAG-3), and galectin-3 (GAL-3), in mismatch repair-deficient (MMRd)/MMR-proficient and abnormal p53 expressing endometrial carcinomas and their relationship with clinical-histopathological features. Patients who underwent surgery for endometrial carcinoma between January 2008 and December 2018 were included in the study. Immunohistochemical analysis of MLH1, PMS2, MSH2, MSH6, p53, PD-L1, VISTA, LAG-3, and GAL-3 was performed on the tissue samples of microarray. A total of 529 patients were included. MMRd and p53-mutant tumors accounted for 31.5% and 11.5% of cases, respectively. PD-L1 and LAG-3 expressions in the MMRd and p53-mutant groups were higher than in the MMR-proficient group (P < 0.001). GAL-3 expression in the MMR-proficient group was statistically higher than in the MMRd and p53-mutant groups (P < 0.001). Mean age, grade, International Federation of Gynecology and Obstetrics stage, lymphovascular invasion, and lymph node metastasis were significantly higher in the p53-mutant group (P < 0.001). In the group with PD-L1 expression, nonendometrioid histologic type, tumor grade, and lymphovascular invasion were significantly higher (P < 0.001). Tumor grade, lymphovascular invasion, lymph node metastasis, and microcystic, elongated and fragmented pattern of invasion were significantly higher in the group with high VISTA expression (P < 0.05). Tumor grade was significantly higher in the group with LAG-3 expression (P < 0.001). Immunohistochemically determined subgroups and PD-L1, VISTA, LAG-3, and GAL-3 expression levels may be useful indicators of molecular features, and clinical outcomes also may have important implications for the development of targeted therapies in endometrial carcinoma.

Effects of chronic sleep deprivation on upper respiratory tract mucosal histology and mucociliary clearance on rats.

In this study, we aimed to investigate the effects of chronic sleep deprivation on mucociliary clearance, which is the primary defence mechanism of the upper airway tract and nasal mucosal histology. Forty-two Wistar Albino rats (250-300 g), 8 or 12 weeks old, were randomly assigned into three groups as follows. The first sleep-deprivation group consisted of 14 rats (A), another 14 of them were assigned to platform group (B), and the remaining 14 were included to the home cage control group (C). For the two deprivation groups (A and B), the modified multiple platform method (MMPM) was used to induce sleep deprivation for 21 days. Tc-99m MAA rhinoscintigraphy was performed to assess mucociliary clearance and the nasal histopathological changes of the sacrificed rats were also examined. Mucociliary clearance was significantly higher in sleep deprivation (A) and deprivation control (B) groups than the control group (C) (p = .037). The ratio of columnar ciliary was significantly higher in group A and B than in the control group (p = .003). The transitional epithelial ratio in groups A and B was also significantly increased compared with group C (p = .04). The control group's squamous epithelial ratio was increased compared to the sleep-deprived groups (p = .003). There was a significantly increased inflammatory response in the ciliated columnar epithelium in groups A and B compared to group C (p = .02). For the first time in the literature, we demonstrated that chronic sleep deprivation has caused a significant increase in mucociliary clearance speed and in the number of ciliary cells.

Comparison of the effects of operating microscopes with light emitting diode and halogen light source on the eye: a rabbit study.

PURPOSE: To evaluate the potential toxicity of operation microscopes with halogen and light emitting diode (LED) light source on the rabbit eyes. MATERIALS AND METHODS: Thirty-two eyes of 16 male New Zealand pigmented rabbits were involved in the study. The rabbits were divided into two groups according to the type of light source applied. Only one eye of each rabbit was exposed to illumination light, unexposed fellow eyes served as the control group. Experimental groups included group 1 exposed to halogen light for 2 h and evaluated 1 day and 1 week after the illumination, group 2 exposed to LED light for two hours and evaluated 1 day and 1 week after the illumination. On the first and seventh days after exposing the light, we evaluated the rabbit corneas using in vivo confocal microscopy (IVCM). At the end of the seventh day, the Hematoxylin-eosin staining and TUNEL staining were performed to investigate the presence of apoptosis in the retina and retina pigment epithelium. RESULTS: Early IVCM findings revealed corneal epithelial cell ovalization and indistinct intercellular borders in the halogen light group. We also observed more increase in the keratocyte density index (23.7% vs 14.1%, p = 0.001, respectively) and the Bowman reflectivity index (12.4% vs 4.1%, p = 0.001, respectively) at first day of the light exposure in halogen light group compared to LED light group. However, late IVCM indicated that these findings disappeared one week later. No apoptosis was observed in the corneal and retinal layers in early and late examination groups. CONCLUSION: The present experimental study demonstrated that both halogen and LED lights, which were commonly used for microscopic eye surgery, had no sustained adverse effect on the cornea and retina of the rabbits; however, halogen light had a temporary adverse effect on corneal epithelium and stroma, which resolved within 1 week.

Identification of major ADH genes in ethanol metabolism of Pichia pastoris.

The methylotrophic yeast Pichia pastoris (syn. Komagataella phaffii) is a successful host widely used in recombinant protein production. The widespread use of a methanol-regulated alcohol oxidase 1 (AOX1) promoter for recombinant protein production has directed studies particularly about methanol metabolism in this yeast. Although there is comprehensive knowledge about methanol metabolism, there are other mechanisms in P. pastoris that have not been investigated yet, such as ethanol metabolism. The gene responsible for the consumption of ethanol ADH2 (XM_002491337, known as ADH3) was identified and characterized in our previous study. In this study, the ADH genes (XM_002489969, XM_002491163, XM_002493969) in P. pastoris genome were investigated to determine their roles in ethanol production by gene disruption analysis. We report that the ADH900 (XM_002491163) is the main gene responsible for ethanol production in P. pastoris. The ADH2 gene, previously identified as the only gene responsible for ethanol consumption, also plays a minor role in ethanol production in the absence of the ADH900 gene. The investigation of the carbon source regulation mechanism has also revealed that the ADH2 gene exhibit similar expression behaviours with ADH900 on glucose, glycerol, and methanol, however, it is strongly induced by ethanol.

Large-scale production of yak (Bos grunniens) chymosin A in Pichia pastoris.

Milk-clotting enzymes used in the dairy industry can be obtained from different sources such as plants, animals, and microorganisms. Recombinant chymosin is the best alternative for the dairy industry due to the differences in physicochemical properties of coagulating enzymes and scarcity of chymosin from animal sources. In this study, glycosylated and non-glycosylated forms of yak chymosin were extracellularly produced in a methylotrophic yeast, Komagataella phaffii (Pichia pastoris). Synthetic yak prochymosin genes were cloned into the pPICZαA vector, expressed in P. pastoris GS115 (PDI) strain. Active chymosin expression was achieved into supernatant with Saccharomyces cerevisiae α-mating factor under the control of methanol-inducible AOXI promoter. The glycosylation of yak chymosin did not have a significant effect on yield and activity at shake flask level. In a 5L fermentor, production of native yak-chymosin was achieved and the enzyme activity was found as 214 IMCU/ml. pH of 6-7 and temperature of 40 °C values were optimum for the enzyme. The laboratory scale white cheese production yield with recombinant yak chymosin was very similar to a commercial bovine chymosin. These results indicate that P. pastoris expression system is very suitable for recombinant yak chymosin production to meet the needs of the cheese industry.

Extracellular production of the recombinant bacterial transglutaminase in Pichia pastoris.

Microbial pro-transglutaminase (pro-MTGase) from Streptomyces mobaraensis was expressed in Pichia pastoris (Komagataella phaffii) under the control of constitutive GAP promoter. The single copy of the gene containing clone was grown in shake flasks to determine the optimum conditions for the production of recombinant pro-MTGase. Three temperature (20 °C, 25 °C, 28 °C) and four pH (5, 6, 7, 7.5) values were evaluated at the shake flask level for the extracellular production of pro-MTGase. The highest enzyme activity was obtained with low temperature (20 °C) and high pH (7.5). The maximum yield was 9120 U/L. For the large-scale extracellular production of pro-MTGase, the clone was cultivated in 5 L bioreactor. The fermentation process was carried out at 20 °C, pH 7 and 20% dissolved oxygen for 79 h. The enzyme activity was calculated as 37640 U/L for large-scale production. These results indicate that P. pastoris expression system is very suitable for recombinant MTGase production under the control of the GAP promoter.

Cloning and expression of pullulanase from Bacillus subtilis BK07 and PY22 in Pichia pastoris.

In this study, pullulanase genes from a wild isolate B. subtilis BK07 and B. subtilis PY22 (mutant strain derived from B. subtilis 168) were transformed into P. pastoris KM71H. Extracellular recombinant protein production was achieved with methanol induction under the regulation of AOX1 promoter utilizing the Saccharomyces cerevisiae α-mating factor sequence for extracellular secretion. The molecular weight of the recombinant enzymes BK07pul and PY22pul were both approximately 90 kDa. Both enzymes showed highest activity at 40 °C, however PY22pul showed optimum activity at pH 6 whereas, BK07pul had highest activity at pH 8. BK07pul and PY22pul activities were determined as 8.46 U/mL and 15 U/mL. The enzyme stability of BK07pul was higher (89%) than PY22pul (68%) where relative activity was determined as activity remaining after 1 h at corresponding optimum conditions for each. Amino acid homology evaluation revealed the two enzymes had 80% identity in primary structure. The presence of conserved sequences consisting of 7 amino acids (YNWGYDP) in both enzymes confirmed these to be type I pullulanases, capable of hydrolyzing α-1,6 glucosidic bonds of pullulan resulting in maltotriose units.

Comparison of ADH3 promoter with commonly used promoters for recombinant protein production in Pichia pastoris.

Recombinant protein production under the control of the PADH3 was compared with Pichia pastoris PAOX1 and PGAP. The single-copy-clones expressing Aspergillus niger xylanase (XylB) gene with the three different promoters were tested in shake flask and 5 L fed-batch fermentation processes. Recombinant protein production with PADH3, PAOX1 and PGAP were initiated by addition of ethanol, methanol and glucose, respectively in the culture medium. The fermentation process was carried out for 72 h at 30 °C, pH 5 and 30% dissolved oxygen. Extracellular protein production yield for PADH3 (3725 U/mL) was higher than for PAOX1 (2095 U/mL) and PGAP (580 U/mL) at fermentor scale under the conditions tested. These results show that the PADH3 promoter is a promising tool for large scale production of recombinant proteins and can be an alternative to the PAOX1 and PGAP.

Impaired Pulmonary Function in Patients with Psoriasis.

BACKGROUND: Psoriasis is associated with chronic obstructive pulmonary disease. There is no study on the spirometric pulmonary function testing in patients with psoriasis. OBJECTIVE: The aim of this study was to compare the spirometric parameters in patients with psoriasis and controls. METHODS: Ninety-six patients with psoriasis and 60 sex- and age-matched control subjects were included in this study. Spirometric pulmonary function testing, including percent forced vital capacity (FVC%), percent forced expiratory volume in the 1st second (FEV1%), forced expiratory flow at 25-75% of FVC (FEF25-75%), and FEV1/FVC ratio, was performed in all study subjects. RESULTS: The mean FEV1/FVC ratio and FEF25-75% were significantly lower in the psoriasis patients than in the controls (82.4 ± 6.3 vs. 90.7 ± 10.7, p < 0.001, and 86.7 ± 24.2 vs. 94.8 ± 23.0, p = 0.04, respectively). Both FEV1/FVC ratio and FEF25-75% were significantly associated with the presence of psoriasis (p < 0.001 and p = 0.029, respectively). CONCLUSION: Psoriasis patients had lower mean FEV1/FVC ratios and FEF25-75%, compared with the control subjects. FEV1/FVC and FEF25-75% are independently associated with the presence of psoriasis.

Functional analysis of alcohol dehydrogenase (ADH) genes in Pichia pastoris.

OBJECTIVES: To characterize the genes responsible for ethanol utilization in Pichia pastoris. RESULTS: ADH3 (XM_002491337) and ADH (FN392323) genes were disrupted in P. pastoris. The ADH3 mutant strain, MK115 (Δadh3), lost its ability to grow on minimal ethanol media but produced ethanol in minimal glucose medium. ADH3p was responsible for 92 % of total Adh enzyme activity in glucose media. The double knockout strain MK117 (Δadh3Δadh) also produced ethanol. The Adh activities of X33 and MK116 (Δadh) strains were not different. Thus, the ADH gene does not play a role in ethanol metabolism. CONCLUSION: The PpADH3 is the only gene responsible for consumption of ethanol in P. pastoris.

Recurrent Sertoli-Leydig cell tumor of ovary in 8-year-old girl.

Sertoli-Leydig cell tumors are rare sex cord-stromal neoplasms that account for <0.2% of ovarian tumors. These tumors with a retiform pattern pose difficult diagnostic problems, with the majority of being misinterpreted as serous papillary cystadenocarcinoma and endodermal sinus tumor. We report an 8-year-old female patient presented to our institution with a huge mass and pain in the lower abdomen and recurrence in the 10th months following the first operation. Only four cases of Sertoli-Leydig cell tumors have been reported under age of the eight years in the literature so far. It is difficult to define the stage and the morphology of Sertoli-Leydig cell tumors with retiform pattern in children and chemotherapy or radiotherapy administration is contraversial. However, fertility sparing surgeries should be considered as a first treatment choice on the time of the diagnosis and the recurrence.

Neutrophil to lymphocyte ratio as a measure of systemic inflammation in psoriasis.

OBJECTIVE: Psoriasis is a chronic systemic inflammatory disorder. The neutrophil to lymphocyte ratio (N/L ratio) has been used as a marker for systemic inflammatory status. In our study, we aimed to evaluate N/L ratio in patients with psoriasis. METHODS: This cross-sectional study population consisted of 138 patients with psoriasis and 120 age- and sex-matched control subjects. RESULTS: The patients had significantly higher neutrophil counts and lower lymphocyte counts than the controls. The N/L ratios and high sensitivity C reactive protein (hs-CRP) levels were also significantly higher in patients. The N/L ratios and hs-CRP levels were increasing with increasing in Psoriasis Area and Severity Index score. Furthermore, the N/L ratios and hs-CRP levels of patients were found to be positively correlated. CONCLUSIONS: Our data show that the N/L ratio to be a simple, inexpensive and easily assessable marker of systemic inflammation in patients with psoriasis.

Immunohistochemical Approach to Mismatch Repair Deficiency in Pediatric High-Grade Glioma.

Knowledge of the molecular pathways of pediatric high-grade gliomas is increasing. Gliomas with mismatch repair deficiency do not currently comprise a distinct group, but data on this topic have been accumulating in recent publications. Immunohistochemistry can effectively determine mismatch repair status, indirectly suggesting the microsatellite instability of the tumor. This study aimed to determine the number of mismatch repair-deficient pediatric high-grade gliomas in a tertiary institution and assess the relationship between the survival and mismatch repair status of the patients. It also aimed to assess the potential for further clinical studies including immunotherapy. Of 24 patients with high-grade gliomas, 3 deceased patients were mismatch repair-deficient. Mismatch repair deficiency was significantly associated with shorter survival ( P =0.004). Immunotherapy trials need to progress, and patients with mismatch repair-deficient pediatric high-grade gliomas are the most suitable candidates for such studies.

Il-6 and MSH3 in colorectal carcinoma: Expression, relationship, and prognostic significance in 171 colorectal carcinoma cases.

AIMS: Colorectal cancer (CRC), the most common type of gastrointestinal cancer, mostly develops as a result of environmental factors. Inflammation is a relatively uncommon but crucial contributor to its etiology, and inflammation is also thought to pose a risk in patients without a clinical diagnosis of inflammatory bowel disease. In cell lines, the proinflammatory cytokine interleukin-6 (IL-6) causes a cytosolic shift in the mismatch repair protein MSH3, accompanied by functional loss. This study aimed to evaluate IL-6 and MSH3 expression in 171 sporadic CRC samples by immunohistochemistry (IHC). High levels of IL-6 are hypothesized to cause MSH3 expression loss. We also explored the clinical/pathological aspects of IHC-detected MSH3 loss and the relationship between MSH3 expression and tumor-infiltrating lymphocytes (TILs). MATERIALS AND METHODS: IL-6 and MSH3 IHC and H and E slides were evaluated by two pathologists. Clinical data were obtained from the institution's database. RESULTS: A relationship between MSH3 loss and IL-6 expression was not proven (P = 0.963). MSH3 staining was significantly reduced in the patient group with high TILs (P = 0.035). We observed 104 CRC cases (60.8%) with IL-6 expression and 85 cases (49.7%) with reduced MSH3 expression. CONCLUSION: This study did not demonstrate an association between IL-6 and MSH3 expression. As MSH3 is a relatively little-known protein, further large-scale studies are needed. The use of IHC to identify patients who may benefit from anti-IL-6 therapies in CRC in the future may be critical.

Effects of mid­gestational sevoflurane and magnesium sulfate on maternal oxidative stress, inflammation and fetal brain histopathology.

Models of inflammation, oxidative stress, hyperoxia and hypoxia have demonstrated that magnesium sulfate (MgSO4), a commonly used drug in obstetrics, has neuroprotective potential. In the present study, the effects of MgSO4 treatment on inflammation, oxidative stress and fetal brain histopathology were evaluated in an experimental rat model following sevoflurane (Sv) exposure during the mid-gestational period. Rats were randomly divided into groups: C (control; no injections or anesthesia), Sv (exposure to 2.5% Sv for 2 h), MgSO4 (administered 270 mg/kg MgSO4 intraperitoneally) and Sv + MgSO4 (Sv administered 30 min after MgSO4 injection). Inflammatory and oxidative stress markers were measured in the serum and neurotoxicity was investigated histopathologically in fetal brain tissue. Short-term mid-gestational exposure to a 1.1 minimum alveolar concentration of Sv did not significantly increase the levels of any of the measured biochemical markers, except for TNF-α. Histopathological evaluations demonstrated no findings suggestive of pathological apoptosis, neuroinflammation or oxidative stress-induced cell damage. MgSO4 injection prior to anesthesia caused no significant differences in biochemical or histopathological marker levels compared to the C and Sv groups. The present study indicated that short-term exposure to Sv could potentially be considered a harmless external stimulus to the fetal brain.

Evaluation of endometrial receptivity in recurrent pregnancy loss and recurrent implantation failure.

Objective: The cause of implantation defects in patients with recurrent implantation failure (RIF) and recurrent pregnancy loss (RPL) has not been clearly established. We aimed to evaluate the immunohistochemical changes in HOXA-11, ß1 integrin, focal adhesion kinase (FAK), cluster of differentiation 44 (CD44), and extracellular matrix protein 1 (ECM1) molecules during the receptive endometrial period in patients with RIF and RPL. Materials and Methods: This study was retrospectively conducted at a university hospital. After the exclusion of cases with pathology that may cause a change in the level of receptors in the endometrium, biopsies performed during the receptive period were selected, and the patients were categorized into RPL (n=15), RIF (n=16), control (n=16) groups. All preparations were immunohistochemically stained for HOXA-11, ß1 integrin, FAK, CD44, and ECM1. Results: HOXA-11 and ß1 Integrin expression changes were similar between the RIF and control groups. However, FAK expression was significantly increased in the RIF group (p<0.01). Additionally, ECM1 and CD44 expressions were significantly decreased in the RIF group compared with the control group (p<0.01). There was no significant difference in the endometrial staining of HOXA-11, FAK, and ECM1 in patients with a history of RPL. However, ß1 Integrin and CD44 levels were significantly decreased in the RPL group compared with the control group (p<0.05). Conclusion: Implantation is a complex process, and altered adhesion mechanisms involved in endometrial receptivity may be related to defective implantation in patients with RIF and RPL. Among the adhesion molecules, the expression of CD44, ß1 integrin, FAK, and ECM1 molecules varies in inappropriate implantation compared with the normal population.

Protective effects of lupeol in rats with renal ischemia­reperfusion injury.

Acute kidney injury (AKI) caused by ischemia and, exogenous or endogenous nephrotoxic agents poses a serious health issue. AKI is seen in 1% of all hospital admissions, 2-5% of hospitalizations and 67% of intensive care unit (ICU) patients. The in-hospital mortality rates for AKI is 40-50, and >50% for ICU patients. Ischemia-reperfusion (I/R) injury in the kidney can activate inflammatory responses and oxidative stress, resulting in AKI. The common endpoint in acute tubular necrosis is a cellular insult secondary to ischemia or direct toxins, which results in effacement of brush border, cell death and decreased function of tubular cells. The aim of the present study was to assess if the reported antioxidant and anti-inflammatory agent lupeol can exert any effects against renal I/R damage. In total, 24 Wistar Albino rats were randomly assigned into four groups of 6, namely Sham, lupeol, ischemia and therapy groups. In the lupeol group, intraperitoneal administration of 100 mg/kg lupeol was given 1 h before laparotomy, whilst only laparotomy was conducted in the sham group. The renal arteries of both kidneys were clamped for 45 min, 1 h after either intraperitoneal saline injection (in the ischemia group) or 100 mg/kg lupeol application (in the therapy group). The blood samples and renal tissues of all rats were collected after 24 h. In blood samples, blood urea nitrogen (BUN) was measured by the urease enzymatic method, and creatinine was measured by the kinetic Jaffe method. Using ELISA method, TNF-α and IL-6 levels were measured in the blood samples, whereas malondialdehyde (MDA), glutathione (GSH), caspase-3 levels were measured in kidney tissues. In addition, kidney histopathological analysis was performed by evaluating the degree of degeneration, tubular dilatation, interstitial lymphocyte infiltration, protein cylinders, necrosis and loss of brush borders. It was determined that renal damage occurred due to higher BUN, creatinine, MDA, TNF-α and caspase-3 values observed in the kidney tissues and blood samples of rats in ischemia group compared with the Sham group. Compared with those in the ischemia group, rats in the therapy group exhibited increased levels of GSH and reduced levels of BUN, TNF-α, MDA. Furthermore, the ischemia group also had reduced histopathological damage scores. Although differences in creatinine, IL-6 and caspase-3 levels were not statistically significant, they were markedly reduced in the treatment group. Taken together, these findings suggest that lupeol can prevent kidney damage as mainly evidenced by the reduced histopathological damage scores, decreased levels of oxidative stress and reduced levels of inflammatory markers. These properties may allow lupeol to be used in the treatment of AKI.

Interstitial Fibrosis as a Common Counterpart of Histopathological Risk Factors in Papillary Thyroid Microcarcinoma: A Retrospective Analysis.

PURPOSE: Interstitial fibrosis in papillary thyroid microcarcinoma is a subject which is under-investigated. The aim of this study is to determine the relationship between interstitial fibrosis, the subtypes of papillary microcarcinoma, and the established prognostic factors. MATERIAL AND METHODS: A total of 75 patients diagnosed with papillary microcarcinoma of the thyroid from January 2011 to December 2020 have been evaluated retrospectively, using demographic features, tumor size, subtype of the tumor, surgical margin status, unifocality, lymphovascular invasion, extracapsular spread and lymph node metastasis as parameters. Hematoxylin and eosin slides were reviewed for interstitial fibrosis. RESULTS: The study includes 13 males and 62 females, in a total of 75 patients. There were 51 patients (68%) with interstitial fibrosis and 24 (32%) patients without interstitial fibrosis. Among them, 45 (60%) were classic, 27 (36%) were follicular variant and 3 (4%) were other subtypes. Interstitial fibrosis is significantly associated with bilaterality (p = 0.023), multifocality (p = 0.004), capsule invasion (p < 0.001) and lymph node metastasis (p = 0.043). Evaluation of tumor sub groups showed significant increased risk of lymphovascular invasion in the follicular variant (p = 0.019). CONCLUSION: Although the relationship of interstitial fibrosis and prognosis of other cancer types has been discussed, there are few studies in the literature regarding its effect on the prognosis of papillary microcarcinoma. Our results show that interstitial fibrosis can be used as a risk factor. However, new studies are needed to clearly reveal the physiopathology of interstitial fibrosis and its effect on tumorigenesis.

Tissue-specific overexpression of systemic RNA interference components limits lifespan in C. elegans.

Intertissue RNA transport recently emerged as a novel signaling mechanism. In mammals, mounting evidence suggests that small RNA transfer between cells is widespread and used in various physiological contexts. In the nematode C. elegans, a similar mechanism is conferred by the systemic RNAi pathway. Members of the Systemic RNA Interference Defective (SID) family act at different steps of cellular RNA uptake and export. The limiting step in systemic RNA interference (RNAi) is the import of extracellular RNAs via the conserved double-stranded (dsRNA)-gated dsRNA channel SID-1. To better understand the role of RNAs as intertissue signaling molecules, we modified the function of SID-1 in specific tissues of C. elegans. We observed that sid-1 loss-of-function mutants are as healthy as wild-type worms. Conversely, overexpression of sid-1 in C. elegans intestine, muscle, or neurons rendered worms short-lived. The effects of intestinal sid-1 overexpression were attenuated by silencing the components of systemic RNAi sid-1, sid-2 and sid-5, implicating systemic RNA signaling in the lifespan reduction. Accordingly, tissue-specific overexpression of sid-2 and sid-5 also reduced worm lifespan. Additionally, an RNAi screen for components of several non-coding RNA pathways revealed that silencing the miRNA biogenesis proteins PASH-1 and DCR-1 rendered the lifespan of worms with intestinal sid-1 overexpression similar to controls. Collectively, our data support the notion that systemic RNA signaling must be tightly regulated, and unbalancing that process provokes a reduction in lifespan. We termed this phenomenon Intercellular/Extracellular Systemic RNA imbalance (InExS).

Thymic carcinoma presenting with overlap polyarthritis and myositis: A rare paraneoplastic syndrome in childhood.

Thymic tumors are very rare neoplasms in children and account for less than 1% of mediastinal tumors in pediatric patients. One-third of the pediatric patients present with symptoms related to the compression of the tumor mass on the surrounding anatomic structures, and paraneoplastic syndromes such as myasthenia gravis, pure red cell aplasia, acquired hypogammaglobulinemia, and connective tissue disorders, which rarely occur in children with thymic tumors. Herein, we report a case of thymic carcinoma mimicking the symptoms of a connective tissue disease with symmetrical polyarthritis accompanying myositis, fever, weight loss, and malaise in a 15-year-old male patient. To our knowledge, this is the first case pediatric thymic carcinoma accompany with severe polyarthritis and myopathy, thus we have reviewed the current literature regarding the cases of thymic malignancies coexisting with paraneoplastic syndromes in children.