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Background Thyroid diseases are highly prevalent worldwide, but their diagnosis remains a challenge. We established reference intervals (RIs) for thyroid-associated hormones and evaluated the prevalence of thyroid diseases in China. Methods After excluding outliers based on the results of ultrasound screening, thyroid antibody tests, and the Tukey method, the medical records of 20,303 euthyroid adults, who visited the Department of Health Care at Peking Union Medical College Hospital from January 2014 to December 2018, were analyzed. Thyroid-associated hormones were measured by the Siemens Advia Centaur XP analyzer. The RIs for thyroid-associated hormones were calculated according to the CLSI C28-A3 guidelines, and were compared with the RIs provided by Siemens. The prevalence of thyroid diseases over the five years was evaluated and compared using the chi-square test. Results The RIs for thyroid stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), total thyroxine (TT4), and total triiodothyronine (TT3) were 0.71-4.92 mIU/L, 12.2-20.1 pmol/L, 3.9-6.0 pmol/L, 65.6-135.1 nmol/L, and 1.2-2.2 nmol/L, respectively. The RIs of all hormones except TT4 differed significantly between males and females. The RIs of TSH increased with increasing age. The prevalence of overt hypothyroidism, overt hyperthyroidism, subclinical hypothyroidism, and subclinical hyperthyroidism was 0.5% and 0.8%, 0.2% and 0.6%, 3.8% and 6.1%, and 3.3% and 4.7% in males and females, respectively, which differed from those provided by Siemens. Conclusions Sex-specific RIs were established for thyroid-associated hormones, and the prevalence of thyroid diseases was determined in the Chinese population.

Background. Associations between iodine intake and thyroid nodules (TNs) were not consistent. We aimed to illustrate the relationship between urinary iodine concentration (UIC) and TNs. Methods. A total of 12,698 participants were enrolled in analysis. All of the participants filled out questionnaires and underwent physical examinations, laboratory tests, and thyroid ultrasonography. UIC, serum thyrotropin (TSH), thyroid peroxidase antibodies (TPOAb), and thyroglobulin antibodies (TgAb) were measured in the central laboratory. Results. The prevalence of TNs was 16.00%, and the median UIC was 206.1 μg/L. TNs and UIC were negatively related when UIC was less than 527 μg/L ( adjusted OR = 0.87 ; 95% CI, 0.80, 0.94), and the relationship between UIC and TNs was not statistically significant when UIC was greater than 527 μg/L ( adjusted OR = 1.25 ; 95% CI, 0.98, 1.60). In women, UIC was negatively associated with risk for TNs (adjusted OR 0.95; 95% CI, 0.91, 0.99). Conclusion. The relationship between TNs and UIC differed between men and women. The risk of TNs decreased with the elevation of UIC in men when UIC was lower than 527 μg/L, while UIC and the presence of TNs were negatively correlated in women. In the future, cohort studies or other studies that can explain causality must be conducted to explore the relationship between iodine status and TNs.

Background Given that both insufficient and excess maternal iodine have adverse consequences such as poor cognitive performance, delayed physical development and increased fetal and infant mortality, the determination of maternal iodine status is very important. In this study, we established and verified a method involving inductively coupled plasma-mass spectrometry (ICP-MS) technology for the rapid determination of the amniotic fluid iodine concentration (AFIC), breast milk iodine concentration (BMIC) and cerebrospinal fluid (CSF) iodine concentration (CSFIC). Method Amniotic fluid, breast milk and CSF were collected from residual samples at Peking Union Medical College Hospital (PUMCH). The linearity, detection limit, precision, recovery, carryover and matrix effect of the testing method using ICP-MS technology were thoroughly evaluated according to the EP-10-A2 evaluation protocol approved by the Clinical and Laboratory Standards Institute (CLSI) guidelines. Furthermore, we evaluated the AFIC, BMIC and CSFIC distributions among clinical patients from PUMCH. Results The correlation coefficient (r) was higher than 0.99 (0.995–1.000). The limit of detection (LOD) was 0.233 µg/L, and the limit of quantification (LOQ) was 0.778 µg/L. For amniotic fluid, breast milk and CSF, the assay repeatabilities were 1.5%–1.8%, 1.9%–4.0% and 1.8%–4.0%, respectively, and the within-laboratory coefficient of variations (CV%) over five days were 3.3%–9.2%, 7.2%–8.0% and 3.2%–7.8%, respectively. The recovery rates ranged from 97.7% to 109.8%. Moreover, the median concentrations of iodine in the amniotic fluid, breast milk and CSF of the patients from PUMCH were 176.3 µg/L, 136.0 µg/L, and 81.8 µg/L, respectively. Conclusion A rapid, stable and accurate method that incorporates ICP-MS technology for the determination of iodine concentration was established for amniotic fluid, breast milk and CSF in this study.

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. 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. 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”. 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.

Both thyroid-stimulating immunoglobulins immunoassay (TSI IA) and thyrotrophin receptor antibody immunoassay (TRAb IA) are commonly used for the diagnosis of Graves’ disease (GD). The aim of the present study was to compare the clinical diagnostic performance of these two methods. Sera were obtained from 1103 subjects presenting a variety of clinical conditions from three centers: 100 subjects with untreated GD, 200 with treated GD, 62 with autoimmune thyroid disease(AIT), 216 with other thyroid diseases (OTHER-T), 214 with non-thyroid autoimmune diseases (NTAD), 191 with other diseases (OD), and 120 healthy subjects (HS). Both TSI and TRAb IAs were performed for all 1013 serum samples. Bioassay was performed for 86 samples whose TSI results were inconsistent the TRAb assay results. Comparing untreated GD patients with the control groups (AIT, NTAD, OTHER-T, OD, and HS) resulted in an area under the curve (AUC) of 0.992 for the TSI IA and 0.989 for the TRAb IA with no statistically significant difference observed between these AUC values (P = 0.2733). The best TSI CDP (clinical decision point) value was 0.42 IU/L. The differences in sensitivity (100% vs. 95%, P = 0.7991) and specificity (97.1% vs. 97.6%, P = 0.9426) between the TSI and TRAb IA were not statistically significant. TSI IA had a higher agreement with the TSI bioassay than TRAb IA. The clinical diagnostic performance of the TSI IA for diagnosing Graves’ disease was very similar to that of the TRAb IA. TSI IA can be used to diagnose GD in the Chinese.

HSPC (hematopoietic stem/progenitor cell) aging was closely associated with the organism aging, senile diseases and hematopoietic related diseases. Therefore, study on HSPC aging is of great significance to further elucidate the mechanisms of aging and to treat hematopoietic disease resulting from HSPC aging. Little attention had been paid to mRNA splicing as a mechanism underlying HSPC senescence. We used our lab’s patented in vitro aging model of HSPCs to analyze mRNA splicing relevant protein alterations with iTRAQ-based proteomic analysis. We found that not only the notable mRNA splicing genes such as SR, hnRNP, WBP11, Sf3b1, Ptbp1 and U2AF1 but also the scarcely reported mRNA splicing relevant genes such as Rbmxl1, Dhx16, Pcbp2, Pabpc1 were significantly down-regulated. We further verified their gene expressions by qRT-PCR. In addition, we reported the effect of Spliceostatin A (SSA), which inhibits mRNA splicing in vivo and in vitro, on HSPC aging. It was concluded that mRNA splicing emerged as an important factor for the vulnerability of HSPC aging. This study improved our understanding of the role of mRNA splicing in the HSPC aging process.

This study performed the first microarray analysis of long-noncoding RNA (lncRNA) and mRNA expression profiles in human steroid-induced avascular necrosis of the femoral head (SAVNFH). Expression levels of lncRNAs and mRNAs in three human SAVNFH samples and three human femoral head fracture samples (controls) were detected using third-generation lncRNA microarrays (KangChen Biotech, Shanghai, China). The fold change, false discovery rate, and P value were utilized to filter genes with significant differential expression in the SAVNFH samples compared with the control samples. In total, there were 1179 upregulated and 3214 downregulated lncRNAs (P2. zerofold, P < 0.05). Meanwhile, 1092 upregulated and 565 downregulated mRNAs were found in the SAVNFH samples compared with the control samples. Then, quantitative real-time polymerase chain reaction was used to confirm the previous microarray results using 8 and 20 selected dysregulated lncRNAs and mRNAs, respectively, and the results generally confirmed the microarray findings. Finally, we used Gene Ontology (GO) and pathway analysis to investigate the functions of the altered mRNAs and their associated GO terms and biological pathways. The Immune system process term (GO:0002376) was the most significantly upregulated GO term, and the Regulation of blood coagulation term (GO:0030193) was the most significantly downregulated GO term in the biological process category for the SAVNFH samples. "Hematopoietic cell lineage - Homo sapiens (human) (Pathway ID: hsa04640)" and "Complement and coagulation cascades - Homo sapiens (human) (Pathway ID: hsa04610)" were the most significantly up- and downregulated pathways in the SAVNFH samples compared with the controls. In conclusion, the differential expression of lncRNAs and mRNAs may be correlated with the pathogenesis of SAVNFH, and these significantly dysregulated lncRNAs and mRNAs may function through networks or participate in several specific biological processes. Further research is needed to understand their exact functions and mechanisms in SAVNFH.

Objective: Epidemiologic studies on the relationship between iodine and thyroid antibodies are inconsistent. Iodine nutrition, genetic, and environmental factors have been shown to modify the effects of iodine on thyroid autoimmunity. We investigated the relationship between urinary iodine concentration (UIC) and thyroglobulin antibodies (TgAbs) in individuals living in iodine-sufficient areas in this cross-sectional study. Methods: A total of 15,008 participants were recruited according to the age range of the population of China in our study. An oral questionnaire was administered to collect basic demographic information. Serum thyrotropin (TSH), thyroid peroxidase antibodies (TPOAbs), TgAbs, and UIC were measured, and thyroid ultrasonography was performed in all subjects. Participants were further divided according to the level of UIC and the status of TgAb, and logistic regression was applied to determine the relationship between UIC and TgAbs. Results: The median UIC of the study population was 205.23 (95% confidence interval lCI], 65.7 to 537.67) μg/L. A total of 17.6% of participants had UIC Conclusion: Low UIC is an independent risk factor for positive TgAb in individuals living in iodine-sufficient areas. Abbreviations: CI = confidence interval; CV = coefficient of variation; FT3 = free triiodothyronine; FT4 = free thyroxine; OR = odds ratio; TgAb = thyroglobulin antibody; TPOAb = thyroid peroxidase antibody; TSH = thyrotropin; UIC = urinary iodine concentration; USI = universal salt iodization

We used RNA-sequencing (RNA-Seq) technology and an old hematopoietic stem and progenitor cells (HSPCs) model in vitro to analyze differential expressions of mismatch repair (MMR)-related genes in aged HSPCs, so as to explore the mechanism of DNA MMR injury in hematopoietic stem cells (HSC) aging. In this study, by combining RNA-seq data and National Center for Biotechnology Information database, we focus on six widely reported MMR genes MSH2, MSH3, MSH6, MLH1, PMS1, PMS2, and five MMR genes with closer ties to HSC aging Pcna, Exo1, Rpa1, Rpa2, and Rpa3 according to the genes functional classification and the related signaling pathway. It is concluded that MMR is closely related to HSC aging. This study provides experimental evidence for future researching MMR in HSC aging.

Purpose This study aimed to clarify the clinical features of and evaluate the treatment efficacy for IgG4-related thyroiditis. Methods Fourteen IgG4-related thyroiditis patients and 42 randomly matched IgG4-related disease (IgG4-RD) patients without thyroiditis in a prospective cohort at the Peking Union Medical College Hospital (PUMCH) were enrolled from 2011 to 2019. Patient demographics, clinical characteristics, laboratory parameters and treatment efficacy were analysed. Results The prevalence of IgG4-related thyroiditis in our cohort was 2.0%. The average patient age was 42.8 ± 14.9 years, and the male: female ratio was 1:1. Goiter (14, 100.0%), hard thyroid (14, 100.0%) and neck compression (5, 35.7%) were the most prevalent onset symptoms observed. IgG4-related thyroiditis was characterized by asymmetric diffuse thyroid enlargement on ultrasound. Thirteen (92.9%) patients had hypothyroidism, and all patients had significantly elevated circulating thyroid antibodies. Compared with patients without thyroiditis, patients with IgG4-related thyroiditis had less submandibular gland involvement and lacrimal gland involvement and lower serum IgG4 and T-IgE levels (P = 0.019, P = 0.022, P = 0.004, and P = 0.006, respectively) and more single-organ involvement (P = 0.011). After treatment, the symptoms were relieved, while the size of the thyroid gland did not change significantly, and levothyroxine as a supplemental therapy was still needed. Conclusions IgG4-related thyroiditis is a distinct subtype of IgG4-RD characterized by positive circulating thyroid antibodies and a high rate of hypothyroidism. Although compression symptoms could be relieved with treatment, the thyroid size did not change significantly, and the damage to thyroid function was often irreversible.

Ectopic thyrotropin-secreting pituitary adenoma (ectopic TSH-oma) is a rare disorder that is easily misdiagnosed in clinical work. We report one patient who presented with hyperthyroidism and a suprasellar mass. In this case, preoperative diagnosis of suprasellar ectopic thyrotropin-secreting pituitary adenoma was challenging. A literature review revealed that a total of 11 patients with ectopic TSH-oma were previously reported, and only our one case was diagnosed in the microadenoma stage. Most of the patients with TSH-oma or ectopic TSH-oma were middle-aged. We described ectopic TSH-oma in a child at length. We recommend that ectopic TSH-oma should be considered in the differential diagnosis of thyrotoxicosis syndrome to achieve an accurate, early diagnosis. The somatostatin suppression test and imaging examinations, such as magnetic resonance imaging and positron emission tomography/magnetic resonance imaging, could contribute to the diagnosis. Once the diagnosis was highly suspected, tumor resection could achieve a satisfying long-term outcome in ectopic TSH-oma.

Interference due to the presence of heterophilic antibodies may lead to falsely low or high analyte concentrations, but falsely elevated values are more common in most immunoassay platforms. We report a case of a 53-y old female patient underwent radical thyroidectomy for thyroid papillary carcinoma and the results of TSH in the Siemens Advia Centaur XP after surgery were not suppressed, ranging from 5.73 and 6.61 μIU/ml.The status of the thyroid was then assessed using 4 assay platforms from Siemens, Abbott, Roche and Beckman.The results of TSH were 5.52, 0.54, 0.12, and0.015 μIU/ml, respectively. After the samples were pretreated with the heterophilic antibody blocker, results given by Siemens, Abbott, and Roche showed significant decreases of 0.003, 0.001, and 0.005 μIU/ml, respectively. Therefore, it was confirmed that the presence of heterophilic antibodies in the patient samples interfered with the TSH measurements in multiple assay systems.Clinicians must be aware of the possible assay interference, including the measurements of FT4, FT3 and TSH, results may be misleading in the presence of heterophilic antibodies, in particular when the results of thyroid function tests do not fit the patient clinical presentation.

Background A large deletion in Xp22.3 can result in contiguous gene syndromes, including X-linked ichthyosis (XLI) and Kallmann syndrome (KS), presenting with short stature, chondrodysplasia punctata, intellectual disability, and strabismus. XLI and KS are caused by the deletion of STS and ANOS1, respectively. Method Two KS patients with XLI were screened to identify possible pathogenic mutations using whole exome sequencing. The clinical characteristics, molecular genetics, treatment outcomes, and genotype-phenotype association for each patient were analyzed. Results We identified a novel 3,923 kb deletion within the Xp22.31 region (chrX: 5810838-9733877) containing STS, ANOS1, GPR143, NLGN4X, VCX-A, PUDP, and PNPLA4 in patient 1, who presented with KS, XLI, obesity, hyperlipidemia, and strabismus. We identified a novel 5,807 kb deletion within the Xp22.31-p22.33 regions (chrX: 2700083-8507807) containing STS, ANOS1, and other 24 genes in patient 2, who presented with KS, XLI, obesity, and strabismus. No developmental delay, abnormal speech development, or autistic behavior were noticed in either patient. Conclusion We identified two novel microdeletions in the X chromosome leading to KS and XLI. These findings contribute to the understanding of the molecular mechanisms that drive contiguous gene syndromes. Our research confirmed that the Kallmann-Ichthyosis phenotype is caused by microdeletions at the chromosome level.

The peptidyl-prolyl cis-trans isomerase, Pin1, acts as a unified signaling hub that is exploited in cancer to activate oncogenes and inactivate tumor suppressors, in particular through up-regulation of c-Myc target genes. However, despite considerable efforts, Pin1 has remained an elusive drug target. Here, we screened an electrophilic fragment library to discover covalent inhibitors targeting Pin1’s active site nucleophile - Cys113, leading to the development of Sulfopin, a double-digit nanomolar Pin1 inhibitor. Sulfopin is highly selective for Pin1, as validated by two independent chemoproteomics methods, achieves potent cellular andin vivotarget engagement, and phenocopies genetic knockout of Pin1. Although Pin1 inhibition had a modest effect on viability in cancer cell cultures, Sulfopin induced downregulation of c-Myc target genes and reduced tumor initiation and tumor progression in murine and zebrafish models of MYCN-driven neuroblastoma. Our results suggest that Sulfopin is a suitable chemical probe for assessing Pin1-dependent pharmacology in cells andin vivo. Moreover, these studies indicate that Pin1 should be further investigated as a potential cancer target.

A majority of patients with resistance to thyroid hormone (RTH) are asymptomatic, whereas some patients show signs of hyperthyroidism, or hypothyroidism, or both. Thyrotoxic periodic paralysis is the most common form of acquired periodic paralysis. However, it has not been reported in a patient with RTH up to now.We evaluated a 36-year-old male patient from China with elevated serum free T4 and free T3 and inappropriately high TSH who presented with periodic paralysis.Clinical, biochemical, and radiological assessments, as well as DNA sequencing, were performed.The patient's laboratory tests revealed the following: TSH, 6.14 mIU/L (0.27-4.2 mIU/L); free T3, 12.85 pmol/L (2.8-7.1 pmol/L); free T4, 33.62 pmol/L (9.05-25.5 pmol/L); and serum SHBG, 19.4 nmol/L (18.3-54.1 nmol/L). No significant suppression of TSH was observed in the rapid TSH suppression test with somatostatin analogs. Compound muscle action potential after exercise of the patient was reduced by 58%. Sequencing of thyroid hormone receptor genes confirmed a C446S mutation in the THRβ gene.This is the first report of periodic paralysis as a new phenotype of RTH syndrome.

Background: The fact that serum thyrotropin (TSH) levels increase with age may influence the diagnosis of thyroid diseases in older adults. This study aimed to establish an age-specific serum TSH r...

The increasing genomic complexity of acute myeloid leukemia (AML), the most common form of acute leukemia, poses a major challenge to its therapy. To identify potent therapeutic targets with the ability to block multiple cancer-driving pathways is thus imperative. The unique peptidyl-prolyl cis-trans isomerase Pin1 has been reported to promote tumorigenesis through upregulation of numerous cancer-driving pathways. Although Pin1 is a key drug target for treating acute promyelocytic leukemia (APL) caused by a fusion oncogene, much less is known about the role of Pin1 in other heterogeneous leukemia.The mRNA and protein levels of Pin1 were detected in samples from de novo leukemia patients and healthy controls using real-time quantitative RT-PCR (qRT-PCR) and western blot. The establishment of the lentiviral stable-expressed short hairpin RNA (shRNA) system and the tetracycline-inducible shRNA system for targeting Pin1 were used to analyze the biological function of Pin1 in AML cells. The expression of cancer-related Pin1 downstream oncoproteins in shPin1 (Pin1 knockdown) and Pin1 inhibitor all-trans retinoic acid (ATRA) treated leukemia cells were examined by western blot, followed by evaluating the effects of genetic and chemical inhibition of Pin1 in leukemia cells on transformed phenotype, including cell proliferation and colony formation ability, using trypan blue, cell counting assay, and colony formation assay in vitro, as well as the tumorigenesis ability using in vivo xenograft mouse models.First, we found that the expression of Pin1 mRNA and protein was significantly increased in both de novo leukemia clinical samples and multiple leukemia cell lines, compared with healthy controls. Furthermore, genetic or chemical inhibition of Pin1 in human multiple leukemia cell lines potently inhibited multiple Pin1 substrate oncoproteins and effectively suppressed leukemia cell proliferation and colony formation ability in cell culture models in vitro. Moreover, tetracycline-inducible Pin1 knockdown and slow-releasing ATRA potently inhibited tumorigenicity of U937 and HL-60 leukemia cells in xenograft mouse models.We demonstrate that Pin1 is highly overexpressed in human AML and is a promising therapeutic target to block multiple cancer-driving pathways in AML.

ObjectivesAlthough several studies have shown that cigarette smoking is associated with thyroid stimulating hormone (TSH), thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TgAb), the exact relationship between smoking and thyroid function is controversial. As little is known about the effects of smoking on TSH, TPOAb and TgAb in Chinese residents. This study aimed to evaluate the association between cigarette smoking and TSH, TPOAb and TgAb in ten-city residents of China.Study designThis was a population-based cross-sectional study.MethodsIn this cross-sectional study, 15,181 subjects from ten major cities of China were investigated. Data regarding demographic characteristics, smoking status and consumption of iodine status were collected using in-person interviews based on a self-designed structured questionnaire. Serum concentrations of TSH, TPOAb and TgAb were measured using electrochemiluminescence immunoassays. Univariate analysis and multivariate linear stepwise regression analyses were used to analyze the data.ResultsThe regular smokers had lower concentrations of TSH, TPOAb and TgAb than occasional smokers, former smokers and never smokers. Multivariate analysis demonstrated that regular smoking was associated with the decreased concentrations of TSH (β = -0.178), TPOAb (β = -0.287) and TGAb (β = -0.453) after adjusting other factors. Furthermore, daily smoking number was significantly associated with the decreased level of TSH (β = -0.045) and TPOAb(β = -0.080), and smoking duration was associated with the decreased TSH level (β = -0.030).ConclusionsOur findings suggest that cigarette smoking is related to a significant decline in the concentrations of TSH, TPOAb and TgAb. In addition, daily smoking number and long-term smoking decrease serum TSH and TPOAb levels. Cigarette smoking plays a significant role in the development of thyroid dysfunction.

One of the two common hallmark lesions of Alzheimer’s disease (AD) brains is neurofibrillary tangles (NFTs), which are composed of hyperphosphorylated tau protein (p-tau). NFTs are also a defining feature of other neurodegenerative disorders and have recently been identified in the brains of patients suffering from chronic traumatic encephalopathy (CTE). However, NFTs are not normally observed in traumatic brain injury (TBI) until months or years after injury. This raises the question of whether NFTs are a cause or a consequence of long-term neurodegeneration following TBI. Two conformations of phosphorylated tau, cis p-tau and trans p-tau, which are regulated by the peptidyl-prolyl isomerase Pin1, have been previously identified. By generating a polyclonal and monoclonal antibody (Ab) pair capable of distinguishing between cis and trans isoforms of p-tau (cis p-tau and trans p-tau, respectively), cis p-tau was identified as a precursor of tau pathology and an early driver of neurodegeneration in AD, TBI and CTE. Histological studies shows the appearance of robust cis p-tau in the early stages of human mild cognitive impairment (MCI), AD and CTE brains, as well as after sport- and military-related TBI. Notably, cis p-tau appears within hours after closed head injury and long before other known pathogenic p-tau conformations including oligomers, pre-fibrillary tangles and NFTs. Importantly, cis p-tau monoclonal antibody treatment not only eliminates cis p-tau induction and tau pathology, but also restores many neuropathological and functional outcome in TBI mouse models. Thus, cis p-tau is an early driver of tau pathology in TBI and CTE and detection of cis p-tau in human bodily fluids could potentially provide new diagnostic and prognostic tools. Furthermore, humanization of the cis p-tau antibody could ultimately be developed as a new treatment for AD, TBI and CTE.

In the past 3 years, 15 patients with resistance to thyroid hormone α (RTHα), nine THRA gene mutations have been reported, reforming classification of RTH. RTHα exhibits distinguished clinical manifestations from RTHβ, including growth retardation, skeletal dysplasia, impaired neurodevelopment, cardiovascular dysfunction, constipation and specific thyroid axis type. This review focuses on possible pathogenesis by revelatory basic science of RTHα animal models in vivo, and patients' mutant thyroid hormone receptor α (TRα) in vitro. Clinical manifestations and L-T4 effects are summarized, showing strong correlation to the severity of mutation mostly within the domain which dominated TR interaction with T3 and its corepressors/coactivators. In particular, we propose the diagnosis clues and promising treatment for clinicians.