Development and validation of the nomogram based on ultrasound, thyroid stimulating hormone, and inflammatory marker in papillary thyroid carcinoma: a case-control study.

Background: The increase in the number of thyroid cancer cases in recent years has increased not only the medical burden but also the potential for overtreatment. Therefore, it is crucial to distinguish papillary thyroid cancer from benign thyroid nodules before surgery when treating thyroid nodules. Methods: The patients were divided into two groups: 117 patients made up the validation cohort and 414 patients made up the primary cohort. As a result of the primary cohort, a preoperative prediction model was developed, which was then validated externally in the validation cohort. Preoperative thyrotropin (thyroid stimulating hormone, TSH), systemic immune-inflammation index (SII), lymphocyte-to-monocyte ratio (LMR), and ultrasonographic features were recorded in both groups. Results: As predictors for the model, the preoperative blood levels of TSH, SII, LMR, echogenicity, margin, calcification, composition, taller-than-wide, and age were chosen. This was the regression equation: Y = -0.070 × (age) + 1.511 × (echogenicity) + 1.664 × (margin) + 1.003 × (calcification) + 0.939 × (composition) + 2.964 × (tall than wide) + 0.305 × (TSH) + 0.558 × (SII) - 1.271 × (LMR) + 0.327. Papillary thyroid carcinoma (PTC) was predicted positively with values of Y ≥0.808. The prediction model's accuracy, sensitivity, and specificity were 88.2%, 85.1%, and 94.9%, respectively. The area under the receiver operating characteristic (ROC) curve was 0.961. The model's external validation produced satisfactory results with accuracy, sensitivity, and specificity of 85.5%, 90.9%, and 75.5%, respectively. Conclusions: Using the preoperative TSH, SII, LMR, and ultrasonographic characteristics, a straightforward and accurate preoperative prediction model for PTC has been developed and validated. The preoperative assessment of PTC in clinical application is enhanced by this approach.

Author Correction: Neuroprotectants attenuate hypobaric hypoxia-induced brain injuries in cynomolgus monkeys.

Following the publication of our paper (Zhang et al., 2020), it has come to our attention that we erroneously listed two funding sources unrelated to this study in the "ACKNOWLEDGEMENTS" section. Hereby, we wish to update the "ACKNOWLEDGEMENTS" section as a correction.

Neuroprotectants attenuate hypobaric hypoxia-induced brain injuries in cynomolgus monkeys.

Hypobaric hypoxia (HH) exposure can cause serious brain injury as well as life-threatening cerebral edema in severe cases. Previous studies on the mechanisms of HH-induced brain injury have been conducted primarily using non-primate animal models that are genetically distant to humans, thus hindering the development of disease treatment. Here, we report that cynomolgus monkeys ( Macacafascicularis) exposed to acute HH developed human-like HH syndrome involving severe brain injury and abnormal behavior. Transcriptome profiling of white blood cells and brain tissue from monkeys exposed to increasing altitude revealed the central role of the HIF-1 and other novel signaling pathways, such as the vitamin D receptor (VDR) signaling pathway, in co-regulating HH-induced inflammation processes. We also observed profound transcriptomic alterations in brains after exposure to acute HH, including the activation of angiogenesis and impairment of aerobic respiration and protein folding processes, which likely underlie the pathological effects of HH-induced brain injury. Administration of progesterone (PROG) and steroid neuroprotectant 5α-androst-3ß,5,6ß-triol (TRIOL) significantly attenuated brain injuries and rescued the transcriptomic changes induced by acute HH. Functional investigation of the affected genes suggested that these two neuroprotectants protect the brain by targeting different pathways, with PROG enhancing erythropoiesis and TRIOL suppressing glutamate-induced excitotoxicity. Thus, this study advances our understanding of the pathology induced by acute HH and provides potential compounds for the development of neuroprotectant drugs for therapeutic treatment.

Liver CEBPß Modulates the Kynurenine Metabolism and Mediates the Motility for Hypoxia-Induced Central Fatigue in Mice.

Central fatigue is defined as a failure of the central nervous system to adequately drive the muscle, manifesting limited development, and maintenance of locomotor activity. A plateau in hypoxia leads to central fatigue and followed by maximal motility recession. However, the underlying mechanism is still unclear. The present study describes a mechanism by which liver CEBPß (CCAAT/enhancer-binding protein beta) induced by hypoxic environment alters the kynurenine (KYN) metabolism and causes the suppression of motility function recession. The activation of CEBPß under hypoxia increases the liver expression of tryptophan dioxygenase, thereby enhancing the conversion of tryptophan into KYN; the KYN metabolite can traverse the blood-brain barrier and result in the suppression of motility function. However, the knockdown of CEBPß by injecting pAAV-shRNA-CEBPß via the hepatic portal vein reduces the KYN production and improves the motility function. KYN is a neurochemical that which restricts the exercise capacity after injection in the basal ganglia in mice. Reducing the plasma KYN protects the brain from hypoxia-induced changes associated with fatigue, and the knockdown liver of CEBPß in mice renders resistance to fatigue post-acute hypoxia or tryptophan treatment. This study reveals resistance to central fatigue as a strategy for acclimatization to hypoxia mediated by transcription factor CEBPß in the liver.

Elevation of autophagy rescues spermatogenesis by inhibiting apoptosis of mouse spermatocytes.

Autophagy and apoptosis are interlocked in an extensive crosstalk. Our previous study demonstrated that hypotonic hypoxia-induced marked apoptosis of a spermatocyte-derived cell line (GC-2). However, whether hypoxia-induced apoptosis is mediated by inhibition of autophagy under hypoxic conditions remains unclear. In this study, GC-2 cells were cultured in 1% O2 and harvested at different time points. Autophagy was determined by acridine orange staining, cyto-ID staining, mCherry-GFP-LC3B adenovirus transfection and Western blotting for various autophagy markers. Apoptosis was detected by TUNEL staining, flow cytometry, JC-1 staining and Western blotting of apoptosis-related proteins. We found that hypoxia-induced apoptosis of GC-2 cells through mitochondrial and death receptor pathways and inhibited autophagic flux in GC-2 cells in a time-dependent manner. However, while marked autolysosome formation was observed in GC-2 cells before 24-h culture in hypoxic conditions, apparent apoptosis was observed only after 24-h culture in hypoxic conditions. Caspase-8 siRNA treatment induced cell survival, accompanied by induction of the mature autophagosome, acidic vesicular organelle formation and autophagic flux. Furthermore, Beclin-1 overexpression markedly attenuated the impairment of spermatogenesis in mice by inhibiting apoptosis of spermatocytes. The results of this study demonstrate that hypoxia inhibits autophagy, which further enhances hypoxia-induced apoptosis of mouse spermatocytes by promoting caspase-8 activation in a time-dependent manner, suggesting that combined application of apoptosis inhibition and autophagy activation might be a therapeutic strategy for treating hypoxia-induced male infertility.

Adropin Is a Key Mediator of Hypoxia Induced Anti-Dipsogenic Effects via TRPV4-CamKK-AMPK Signaling in the Circumventricular Organs of Rats.

Water intake reduction (anti-dipsogenic effects) under hypoxia has been well established, but the underlying reason remains unknown. Our previous report indicated that activated TRPV4 neurons in SFO are associated with anti-dipsogenic effects under hypoxia. Although low partial pressure of blood oxygen directly activates TRPV4, humoral factors could also be involved. In the present study, we hypothesize that adropin, a new endogenous peptide hormone, was rapidly increased (serum and brain) concomitant with reduced water intake in early hypoxia. Also, the nuclear expression of c-Fos, a marker for neuronal activation, related to water-consumption (SFO and MnPO) was inhibited. These effects were mitigated by a scavenger, rat adropin neutralizing antibody, which effectively neutralized adropin under hypoxia. Interestingly, injection of recombinant adropin in the third ventricle of the rats also triggered anti-dipsogenic effects and reduced c-Fos positive cells in SFO, but these effects were absent when TRPV4 was knocked down by shRNA. Moreover, adropin-activated CamKK-AMPK signaling related to TRPV4 calcium channel in SFO in normoxia. These results revealed that dissociative adropin was elevated in acute hypoxia, which was responsible for anti-dipsogenic effects by altering TRPV4-CamKK-AMPK signaling in SFO.