Open posterior approach versus endoscopic approach for thoracic ligamentum flavum ossification: a systematic review and meta-analysis.

BACKGROUND: Thoracic ossification of the ligamentum flavum (TOLF), a rare condition more prevalent in East Asia, is managed through open and endoscopic surgical approaches. Determining the superior surgical option remains unclear. This study assesses the safety and clinical outcomes associated with these approaches in TOLF patients. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a systematic literature search up to August 5, 2023, across PubMed, Scopus, EMBASE, Web of Science, Cochrane, and ClinicalTrials.gov. We included randomized controlled trials and cohort studies reporting complication rates, mJOA (modified Japanese Orthopedic Association) scores, JOA scores, VAS (Visual Analog Scale) scores, or hospitalization duration for both open and endoscopic surgeries in TOLF patients. RESULTS: We analyzed 37 studies encompassing 1,646 TOLF patients using a random-effects model. Our findings revealed a significant difference in complication rates (overall complication rates: 0.12; 95% CI: 0.07, 0.19; p < 0.01; I2: 69%; quality of evidence: moderate), with lower complication rates in the endoscopy group. However, no significant differences were observed in JOA scores (overall JOA: 8.35; 95% CI: 7.16, 9.54; p = 0.12; I2: 99%; quality of evidence: very low), VAS scores (overall VAS: 1.31; 95% CI: 1.03, 1.59; p = 0.35; I2: 91%; quality of evidence: very low), or hospitalization duration (hospital stay: 10.83 days; 95% CI: 6.86, 14.80; p = 0.35; I2: 91%; quality of evidence: very low) between the open and endoscopic groups. CONCLUSIONS: This meta-analysis reports lower complication rates and improved postoperative mJOA scores for endoscopic surgery in TOLF patients compared to open surgery. It represents the first comprehensive evaluation of clinical outcomes and safety of different surgical approaches for TOLF patients. Further randomized controlled trials are essential to validate these findings.

Nardilysin-regulated scission mechanism activates polo-like kinase 3 to suppress the development of pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) develops through step-wise genetic and molecular alterations including Kras mutation and inactivation of various apoptotic pathways. Here, we find that development of apoptotic resistance and metastasis of KrasG12D-driven PDAC in mice is accelerated by deleting Plk3, explaining the often-reduced Plk3 expression in human PDAC. Importantly, a 41-kDa Plk3 (p41Plk3) that contains the entire kinase domain at the N-terminus (1-353 aa) is activated by scission of the precursor p72Plk3 at Arg354 by metalloendopeptidase nardilysin (NRDC), and the resulting p32Plk3 C-terminal Polo-box domain (PBD) is removed by proteasome degradation, preventing the inhibition of p41Plk3 by PBD. We find that p41Plk3 is the activated form of Plk3 that regulates a feed-forward mechanism to promote apoptosis and suppress PDAC and metastasis. p41Plk3 phosphorylates c-Fos on Thr164, which in turn induces expression of Plk3 and pro-apoptotic genes. These findings uncover an NRDC-regulated post-translational mechanism that activates Plk3, establishing a prototypic regulation by scission mechanism.

Examining the Impact of the Current Reimbursement Regulation on Patient Access to Innovative Medical Devices in Taiwan: Insights From 8 Years' Reimbursement Data.

OBJECTIVES: This study aimed to assess the impact of the reimbursement regulation of medical devices (Regulation), introduced by the National Health Insurance Administration (NHIA) in 2013, on patients' access to innovative medical devices in Taiwan. METHODS: Analysis of the amount of time needed from application for NHIA reimbursement for new medical devices to receiving the decision from NHIA was done using the nonreimbursement product list featured on the NHIA website. Additionally, Welch analysis of variance was used to compare the amount of time it took from application to NHIA with reimbursement decisions made by the NHIA for different nonreimbursement code categories. Further, related Pharmaceutical Benefit Reimbursement Scheme meeting minutes were analyzed to obtain more detailed information concerning medical devices' reimbursement or not. RESULTS: From December 2012 to June 2021, the overall reimbursement percentage was 56.7%, and the average amount of time between application and reimbursement was 856.7 ± 474.7 days. The mandatory reimbursement rate was about 45%. NHIA reimbursement decisions as special medical devices also take a longer amount of time, because the applicants need to agree to the decision (P < .05). The NHIA decision-making process for nonreimbursement medical devices requires a significantly longer amount of time than for general materials (eg, suture, etc) decisions. CONCLUSIONS: Although the Regulation resolves payment issues, it also increases the amount of time to reach reimbursement decisions, thus hindering patient access to innovative medical devices. The study suggests that the review process needs to be simplified concerning reimbursement notification, using local real-world data to support reimbursement decisions.

Long-term safety of total knee arthroplasty in patients with chronic kidney disease in Taiwan: a retrospective cohort study.

BACKGROUND: Chronic kidney disease (CKD) is a prevalent condition in Taiwan, and the incidence of total knee arthroplasty (TKA) is on the rise. This study aimed to evaluate the postoperative results of patients with different degrees of CKD after TKA, using data from the Taiwan National Health Insurance Research Database. METHODS: The study analyzed 3,078 patients who received TKA from 2012 to 2017, equally divided into three groups: none-CKD, mild CKD (without dialysis), and severe CKD (with dialysis). Propensity score matching was used to minimize selection bias. RESULTS: After TKA, there was no significant difference in the risk of debridement surgery for infection between the three groups (adjusted HR of mild CKD 0.71 95% CI = 0.36 - 1.38, P = 0.3073; adjusted HR of severe CKD: 1.14, 95% CI = 0.63 - 2.06, P = 0.6616). However, CKD patients requiring dialysis had a significantly higher risk of mortality (adjusted HR 1.98, 95% CI = 1.57 - 2.50, P < 0.001) and readmission within 90 days of any causes (adjusted HR 1.83, 95% CI = 1.48 - 2.26, P < 0.001) than non-CKD and mild CKD patients. CONCLUSION: Severe CKD patients needing dialysis after TKA have a higher risk of mortality and readmission rates than that of the non-CKD or mild CKD patients. If the patient is in the early stage of CKD, their prognosis after receiving TKA is expected to be as good as non-CKD patients. LEVEL OF EVIDENCE: IV; well-designed cohort study.

The Association between Uric Acid and Metabolic Syndrome in a Middle-Aged and Elderly Taiwanese Population: A Community-Based Cross-Sectional Study.

BACKGROUND: Metabolic syndrome (MetS) is a prevalent health condition in Taiwan that places individuals at higher risk of cardiovascular disease, diabetes, and stroke. Therefore, the identification of risk factors associated with MetS is crucial. The aim of this study was to investigate the association of uric acid and MetS in a Taiwanese community with a middle-aged and elderly population. METHODS: This cross-sectional study enrolled residents aged 50-90 years living in one community. All of the subjects received a standardized personal interview, including a structured questionnaire, anthropometric measurements, and blood samples were collected for laboratory testing. MetS was defined as excess waist circumference, high blood pressure, high blood sugar, high serum triglycerides, and low serum high-density lipoprotein (HDL). Multiple logistic regression models were used to evaluate uric acid tertiles associated with MetS. RESULTS: A total of 400 subjects were enrolled in the analysis. The overall prevalence of MetS was 35.8%. The prevalence of MetS increased gradually with increasing serum uric acid levels (p value < 0.001). A significant association between uric acid and cardiometabolic risk factors was confirmed, with a Pearson's correlation coefficient for waist circumference of 0.30 (p < 0.001), a coefficient for systolic blood pressure of 0.13 (p = 0.01), a coefficient for triglycerides of 0.33 (p < 0.001), and a coefficient for high-density lipoprotein of -0.30 (p < 0.001). The adjusted odds ratio (OR) of the high uric acid tertile level for MetS was 2.48 (95% CI = 1.31-4.71, p = 0.01). The area under the ROC curve (AUC) for uric acid in predicting MetS was 0.621 (p < 0.001). CONCLUSIONS: The prevalence of MetS in our study population is high. High serum uric acid levels are independently associated with the presence of MetS among the middle-aged and elderly Taiwanese population.

The Relationship between Self-Reported Sitting Time and Vitamin D Levels in Middle-Aged and Elderly Taiwanese Population: A Community-Based Cross-Sectional Study.

(1) Background: Many studies have revealed a relationship between serum 25-hydroxy vitamin D and physical activity. This study aimed to investigate the relationship between self-reported sitting time and serum 25-hydroxy vitamin D levels in middle-aged and elderly adults in Taiwan. (2) Methods: A total of 396 people were enrolled in our study during a community health examination in Taiwan in 2019. We grouped participants from low to high according to their tertile of serum 25-hydroxy vitamin D levels, using the following categories: deficiency, insufficiency, and sufficiency. Parameters including self-reported sitting time were analyzed between each group. Pearson correlation coefficients were calculated to explore the relationships of serum 25-hydroxy vitamin D levels with age-adjusted risk factors. A scatter plot demonstrated the relationship between serum 25-hydroxy vitamin D levels and self-reported sitting time. The association between serum 25-hydroxy vitamin D levels and self-reported sitting time was assessed by multivariate linear regression with adjustment for age, sex, waist circumference, low-density lipoprotein, triglycerides, and smoking and drinking status. (3) Results: We analyzed the data from 396 participants. A total of 41.4% of participants were male, and the average age of all participants was 64.91 (±8.80) years. The participants in the high serum 25-hydroxy vitamin D group were more likely to have shorter self-reported sitting time. Serum 25-hydroxy vitamin D was negatively correlated (Pearson's r) with self-reported sitting time, even after adjustment for age. According to the results of multivariate linear regression, vitamin D levels showed a negative association with self-reported sitting time (ß = -0.131, p = 0.006) after adjustment for age, sex, waist circumference, low-density lipoprotein, triglycerides, and smoking and drinking status. (4) Conclusions: According to our research, self-reported sitting time was inversely correlated with serum 25-hydroxy vitamin D in middle-aged and elderly people in Taiwan. Meanwhile, longer self-reported sitting time can be an independent risk factor for lower serum 25-hydroxy vitamin D levels.

Willow Bark (Salix spp.) Used for Pain Relief in Arthritis: A Meta-Analysis of Randomized Controlled Trials.

This study intends to assess the analgesic effects, physical facilitation, and safety of willow bark use in patients with arthritis. Our study was conducted based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. PubMed, Scopus, EMBASE, Web of Science, Cochrane, and ClinicalTrials.gov were searched for relative randomized controlled trials (RCTs) describing the efficacy or adverse events of willow bark in patients with arthritis until 12 April 2023. We used Cochrane ROB 2.0 and the Grading of Recommendations, Assessment, Development, and Evaluations system to evaluate the quality of studies and evidence. The meta-analysis was carried out by the fix-effects model. This study included five studies with six RCTs consisting of 329 patients with arthritis. The results showed significant differences in pain relief and improvement in physical status for patients with arthritis between willow bark treatment and placebo groups, and no significant differences in the risk of all adverse events in patients with arthritis between willow bark treatment and placebo. Owing to the potential bias, the certainty and evidence of our findings are still inadequate. Therefore, further RCTs are needed to confirm our results.

Analgesic efficacy of collagen peptide in knee osteoarthritis: a meta-analysis of randomized controlled trials.

BACKGROUND: The management of knee osteoarthritis involves various treatment strategies. It is important to explore alternative therapies that are both safe and effective. Collagen peptides have emerged as a potential intervention for knee osteoarthritis. This study aims to evaluate the analgesic effects and safety of collagen peptide in patients diagnosed with knee osteoarthritis. METHODS: We conducted a systematic literature search following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Multiple databases including PubMed, Scopus, EMBASE, Web of Science, Cochrane, and ClinicalTrials.gov were searched for randomized controlled trials (RCTs) published up to 27 May 2023 that focused on the analgesic outcomes and adverse events associated with collagen peptides or hydrolyzed collagen in patients with osteoarthritis. We assessed the quality of the included studies and the strength of evidence using the Cochrane ROB 2.0 tool and Grading of Recommendations, Assessment, Development, and Evaluations. RESULTS: Four trials involving 507 patients with knee osteoarthritis were included and analyzed using the random-effects model. All these trials were considered to have a high risk of bias. Our results revealed a significant difference in pain relief between the collagen peptide group and the placebo group in patients with knee osteoarthritis (standardized mean difference: - 0.58; 95% CI - 0.98, - 0.18, p = 0.004; I2: 68%; quality of evidence: moderate). However, there was no significant difference in the risk of adverse events between collagen peptide and placebo (odds ratio: 1.66; 95% CI 0.99, 2.78, p = 0.05; I2: 0%; quality of evidence: very low). CONCLUSIONS: Our findings demonstrate significant pain relief in patients with knee osteoarthritis who received collagen peptides compared to those who received placebo. In addition, the risk of adverse events did not differ significantly between the collagen peptide group and the placebo group. However, due to potential biases and limitations, well-designed randomized controlled trials are needed to validate and confirm these findings.

A Novel Technique for Autograft Preparation Using Patient-Specific Instrumentation (PSI) Assistance in Total Hip Arthroplasty in Developmental Dysplasia of Hip (DDH).

Due to the change in the structure of the proximal femur and acetabulum in patients with developmental dysplasia of the hip, total hip arthroplasty (THA) was difficult to perform for surgeons. To elevate the acetabular coverage rate, we developed a technique in the use of a patient-specific instrumentation (PSI) graft in patients with developmental dysplasia of hip (DDH) undergoing surgery. This study aims to evaluate the peri-operative outcomes of THA with PSI graft in patients with DDH. This study recruited 6 patients suffering from Crowe I DDH with secondary Grade IV osteoarthritis. All the patients underwent THA with PSI graft performed by a well-experienced surgeon. Perioperative outcomes included surgical procedures, blood loss during operation, the volume of blood transfusion, length of hospitalization, complications, and the mean difference in hemoglobin levels before and after surgery. All the outcomes analyzed were assessed by mean and standard deviation. The average duration of the surgical procedure was found to be 221.17 min, with an SD of 19.65 min. The mean blood loss during the operation was 733.33 mL, with an SD of 355.90 mL. The mean length of hospital stay was calculated to be 6 days, with an SD of 0.89 days. Furthermore, the mean difference between the pre- and postoperative hemoglobin levels was 2.15, with an SD of 0.99. A total of three patients received 2 units of leukocyte-poor red blood cells (LPR) as an accepted blood transfusion. There were no reported complications observed during the admission and one month after the operation. This study reported the peri-operative outcomes in the patients with DDH who underwent THA with PSI graft. We found that THA with PSI graft would provide a safe procedure without significant complications. We assumed that the PSI graft in THA may increase the coverage rate of the acetabulum, which may increase the graft union rates. Further cohort studies and randomized controlled trials were needed to confirm our findings.

The Effect of Congruent Tibial Inserts in Total Knee Arthroplasty: A Network Meta-Analysis of Randomized Controlled Trials.

Objective: The aim of this study was to determine whether modern congruent tibial inserts are associated with superior outcomes in total knee arthroplasty (TKA). Background: Ultracongruent fixed-bearing (UCFB) and medial congruent fixed-bearing (MCFB) inserts have been known to be effective in total knee arthroplasty with patient satisfaction. Nonetheless, no supporting evidence to date exists to rank the clinical outcomes of these various congruent inserts in TKA compared with other important considerations in TKA including cruciate-retaining fixed-bearing (CRFB) and posterior-stabilized fixed-bearing (PSFB) inserts. Methods: We searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, and Scopus up to 15 May 2022. We selected studies involving an active comparison of UCFB or MCFB in TKAs. We performed a network meta-analysis (NMA) of randomized controlled trials (RCTs) and compared different congruent inserts. We ranked the clinical outcomes by SUCRA score with the estimate of the best treatment probability. Our primary outcomes were revision rates and radiolucent lines. Secondary outcomes were functional scores, including the range of motion (ROM), the Knee Society Score (KSS), the Oxford Knee Score (OKS), and WOMAC. Results: Eighteen RCTs with 1793 participants were analyzed. Our NMA ranked MCFB, CRFB, and UCFB with the lowest revision rates. CRFB and UCFB had the fewest radiolucent lines. UCFB had overall the best ROM. UCFB and MCFB had the best OKS score overall. Conclusions: The ranking probability for better clinical outcomes in congruent inserts demonstrated the superiority of congruent tibial inserts, including UCFB and MCFB. UCFB may be associated with better ROM and postoperative functional outcomes. However, integrating future RCTs for high-level evidence is necessary to confirm these findings.

Disease modeling and gene correction of LGMDR21 iPSCs elucidates the role of POGLUT1 in skeletal muscle maintenance, regeneration, and the satellite cell niche.

Autosomal recessive limb-girdle muscular dystrophy 21 (LGMDR21) is caused by pathogenic variants in protein O-glucosyltransferase 1 (POGLUT1), which is responsible for O-glucosylation of specific epidermal growth factor (EGF) repeats found in ∼50 mammalian proteins, including Notch receptors. Previous data from patient biopsies indicated that impaired Notch signaling, reduction of muscle stem cells, and accelerated differentiation are probably involved in disease etiopathology. Using patient induced pluripotent stem cells (iPSCs), their corrected isotypes, and control iPSCs, gene expression profiling indicated dysregulation of POGLUT1, NOTCH, muscle development, extracellular matrix (ECM), cell adhesion, and migration as involved pathways. They also exhibited reduced in vitro POGLUT1 enzymatic activity and NOTCH signaling as well as defective myogenesis, proliferation, migration and differentiation. Furthermore, in vivo studies demonstrated significant reductions in engraftment, muscle stem cell formation, PAX7 expression, and maintenance, along with an increased percentage of mislocalized PAX7+ cells in the interstitial space. Gene correction in patient iPSCs using CRISPR-Cas9 nickase led to the rescue of the main in vitro and in vivo phenotypes. These results demonstrate the efficacy of iPSCs and gene correction in disease modeling and rescue of the phenotypes and provide evidence of the involvement of muscle stem cell niche localization, PAX7 expression, and cell migration as possible mechanisms in LGMDR21.

Molecular mechanisms of snoRNA-IL-15 crosstalk in adipocyte lipolysis and NK cell rejuvenation.

Obesity, in which the functional importance of small nucleolar RNAs (snoRNAs) remains elusive, correlates with risk for many cancer types. Here, we identify that the serum copies of adipocyte-expressed SNORD46 correlate with body mass index (BMI), and serum SNORD46 antagonizes interleukin-15 (IL-15) signaling. Mechanically, SNORD46 binds IL-15 via G11, and G11A (a mutation that significantly enhances binding affinity) knockin drives obesity in mice. Functionally, SNORD46 blocks IL-15-induced, FER kinase-dependent phosphorylation of platelet glycoprotein 4 (CD36) and monoglyceride lipase (MGLL) in adipocytes, leading to inhibited lipolysis and browning. In natural killer (NK) cells, SNORD46 suppresses the IL-15-dependent autophagy, leading to reduced viability of obese NK. SNORD46 power inhibitors exhibit anti-obesity effects, concurring with improved viability of obese NK and anti-tumor immunity of CAR-NK cell therapy. Hence, our findings demonstrate the functional importance of snoRNAs in obesity and the utility of snoRNA power inhibitors for antagonizing obesity-associated immune resistance.

Plumbing mysterious RNAs in "dark genome" for the conquest of human diseases.

Next-generation sequencing has revealed that less than 2% of transcribed genes are translated into proteins, with a large portion transcribed into noncoding RNAs (ncRNAs). Among these, long noncoding RNAs (lncRNAs) represent the largest group and are pervasively transcribed throughout the genome. Dysfunctions in lncRNAs have been found in various diseases, highlighting their potential as therapeutic, diagnostic, and prognostic targets. However, challenges, such as unknown molecular mechanisms and nonspecific immune responses, and issues of drug specificity and delivery present obstacles in translating lncRNAs into clinical applications. In this review, we summarize recent publications that have explored lncRNA functions in human diseases. We also discuss challenges and future directions for developing lncRNA treatments, aiming to bridge the gap between functional studies and clinical potential and inspire further exploration in the field.

Decoding the regulatory roles of non-coding RNAs in cellular metabolism and disease.

Non-coding RNAs, including long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are being studied extensively in a variety of fields. Their roles in metabolism have received increasing attention in recent years but are not yet clear. The regulation of glucose, fatty acid, and amino acid metabolism is an imperative physiological process that occurs in living organisms and takes part in cancer and cardiovascular diseases. Here, we summarize the important roles played by non-coding RNAs in glucose metabolism, fatty acid metabolism, and amino acid metabolism, as well as the mechanisms involved. We also summarize the therapeutic advances for non-coding RNAs in diseases such as obesity, cardiovascular disease, and some metabolic diseases. Overall, non-coding RNAs are indispensable factors in metabolism and have a significant role in the three major metabolisms, which may be exploited as therapeutic targets in the future.

Epidemiology of Oral Cancer in Taiwan: A Population-Based Cancer Registry Study.

Oral cancer (OC) is one of the most common cancers worldwide, and its incidence has regional differences. In this study, the cancer registry database obtained from 1980 to 2019 was used to analyze the characteristic of incidence of OC by average annual percentage change (AAPC) and an age-period-cohort model. Spearman's correlation was used to analyze the relationship between the age-standard incidence rates (ASR) of OC and related risk factors. Our results showed that the ASR of OC increased from 4.19 to 27.19 per 100,000 population with an AAPC of 5.1% (95% CI = 3.9-6.3, p value < 0.001) in men and from 1.16 to 2.8 per 100,000 population with an AAPC of 3.1% (95% CI = 2.6-3.6, p value < 0.001) in women between 1980-1984 and 2015-2019. The age-period-cohort model reported a trend of rising then declining for the rate ratio in men, with peaks occurring in the 1975 cohort, with a rate ratio of 6.80. The trend of incidence of oral cancer was related to changes in the consumption of cigarettes and alcohol and production of betel quid, with r values of 0.952, 0.979 and 0.963, respectively (all p values < 0.001). We strongly suggest avoiding these risk factors in order to prevent OC.

The Non-Coding RNA Journal Club: Highlights on Recent Papers-12.

We are delighted to share with you our twelfth Journal Club and highlight some of the most interesting papers published recently [...].

LIFR recruits HGF-producing neutrophils to promote liver injury repair and regeneration.

The molecular links between tissue repair and tumorigenesis remain elusive. Here, we report that loss of the liver tumor suppressor Lifr in mouse hepatocytes impairs the recruitment and activity of reparative neutrophils, resulting in the inhibition of liver regeneration after partial hepatectomy or toxic injuries. On the other hand, overexpression of LIFR promotes liver repair and regeneration after injury. Interestingly, LIFR deficiency or overexpression does not affect hepatocyte proliferation ex vivo or in vitro . In response to physical or chemical damage to the liver, LIFR from hepatocytes promotes the secretion of the neutrophil chemoattractant CXCL1 (which binds CXCR2 to recruit neutrophils) and cholesterol in a STAT3-dependent manner. Cholesterol, in turn, acts on the recruited neutrophils to secrete hepatocyte growth factor (HGF) to accelerate hepatocyte proliferation and regeneration. Altogether, our findings reveal a LIFR-STAT3- CXCL1-CXCR2 axis and a LIFR-STAT3-cholesterol-HGF axis that mediate hepatic damage- induced crosstalk between hepatocytes and neutrophils to repair and regenerate the liver.

Tumor-associated nonmyelinating Schwann cell-expressed PVT1 promotes pancreatic cancer kynurenine pathway and tumor immune exclusion.

One of the major obstacles to treating pancreatic ductal adenocarcinoma (PDAC) is its immunoresistant microenvironment. The functional importance and molecular mechanisms of Schwann cells in PDAC remains largely elusive. We characterized the gene signature of tumor-associated nonmyelinating Schwann cells (TASc) in PDAC and indicated that the abundance of TASc was correlated with immune suppressive tumor microenvironment and the unfavorable outcome of patients with PDAC. Depletion of pancreatic-specific TASc promoted the tumorigenesis of PDAC tumors. TASc-expressed long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (PVT1) was triggered by the tumor cell-produced interleukin-6. Mechanistically, PVT1 modulated RAF proto-oncogene serine/threonine protein kinase-mediated phosphorylation of tryptophan 2,3-dioxygenase in TASc, facilitating its enzymatic activities in catalysis of tryptophan to kynurenine. Depletion of TASc-expressed PVT1 suppressed PDAC tumor growth. Furthermore, depletion of TASc using a small-molecule inhibitor effectively sensitized PDAC to immunotherapy, signifying the important roles of TASc in PDAC immune resistance.

Hormonal therapies up-regulate MANF and overcome female susceptibility to immune checkpoint inhibitor myocarditis.

Immune checkpoint inhibitors (ICIs) have been increasingly used in combination for cancer treatment but are associated with myocarditis. Here, we report that tumor-bearing mice exhibited response to treatment with combinatorial anti-programmed cell death 1 and anti-cytotoxic T lymphocyte antigen-4 antibodies but also presented with cardiovascular toxicities observed clinically with ICI therapy, including myocarditis and arrhythmia. Female mice were preferentially affected with myocarditis compared to male mice, consistent with a previously described genetic model of ICI myocarditis and emerging clinical data. Mechanistically, myocardial tissue from ICI-treated mice, the genetic mouse model, and human heart tissue from affected patients with ICI myocarditis all exhibited down-regulation of MANF (mesencephalic astrocyte-derived neurotrophic factor) and HSPA5 (heat shock 70-kDa protein 5) in the heart; this down-regulation was particularly notable in female mice. ICI myocarditis was amplified by heart-specific genetic deletion of mouse Manf and was attenuated by administration of recombinant MANF protein, suggesting a causal role. Ironically, both MANF and HSPA5 were transcriptionally induced by liganded estrogen receptor ß and inhibited by androgen receptor. However, ICI treatment reduced serum estradiol concentration to a greater extent in female compared to male mice. Treatment with an estrogen receptor ß-specific agonist and androgen depletion therapy attenuated ICI-associated cardiac effects. Together, our data suggest that ICI treatment inhibits estradiol-dependent expression of MANF/HSPA5 in the heart, curtailing the cardiomyocyte response to immune injury. This endocrine-cardiac-immune pathway offers new insights into the mechanisms of sex differences in cardiac disease and may offer treatment strategies for ICI myocarditis.

Secular trends of intrahepatic cholangiocarcinoma in a high endemic area: A population-based study.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is one of the most aggressive malignancies. However, because of its scarcity there are limited population-based data available for investigations into its epidemiologic characteristics. In Taiwan, we have a national cancer registry database that can be used to evaluate the secular trends of ICC. AIM: To evaluate secular trends of ICC according to age, sex, and risk factors in Taiwan. METHODS: In this population-based study, we used the national Taiwan Cancer Registry database. Age-standardized and relative percent changes in incidence rates were used to describe secular trends in incidence rates and sex ratios of ICC in Taiwan. RESULTS: The age-standardized ICC incidence rate among males increased from 1.51 per 100000 in 1993-1997 to 4.07 per 100000 in 2013-2017 and among female from 1.73 per 100000 to 2.95 per 100000. The incidence in females tended to plateau after 2008-2012. For males, the ICC incidence increased as age increased. In the long-term incidence trend of ICC in females, the incidence of the four age groups (40-44, 45-49, 50-54 and 55-59 years) remained stable in different years; although, the incidence of the 60-64 group had a peak in 2003-2007, and the peak incidence of the 65-69 and 70-74 groups occurred in 2008-2012. Among males, beginning at the age of 65, there were increases in the incidence of ICC for the period of 2003-2017 as compared with females in the period of 2003-2017. CONCLUSION: Increased incidence of ICC occurred in Taiwan over the past two decades. The increased incidence has progressively shifted toward younger people for both males and females.