Pharmacological effects of MT-1207 in bilateral renal artery stenosis hypertension and its hypotensive targets validation.

MT-1207 (MT) as a new antihypertensive drug is under clinical trial. However, its hypotensive mechanism has not been experimentally explored, and it is unknown whether MT can be used for bilateral renal artery stenosis hypertension. Using two-kidney two-clip (2K2C) to mimic bilateral renal artery stenosis in rats, a stroke-prone renovascular hypertension model, the present study further verified its antihypertensive effect, cardiovascular and renal protection, mortality reduction and lifespan prolongation, as well as demonstrated its two novel pharmacological effects for uric acid-lowering and cognition-improving. Notably, MT did not aggravate renal dysfunction; instead, it had beneficial effects on reducing serum uric acid level and maintaining serum K+ at a relatively stable level in 2K2C rats. In contrast, angiotensin receptor blocker losartan aggravated renal dysfunction in 2K2C rats. Mechanistically, MT hypotensive effect was dependent on its blockade of α1 and 5-HT2 receptors, since MT pretreatment abolished these receptor agonists-induced blood pressure elevations in vivo. Further evidence showed MT bound to and interacted with these receptor subtypes including α1A, α1B, α1D, 5-HT2A, 5-HT2B, and 5-HT2C receptors known for control of blood pressure. In conclusion, MT may be used for treatment of bilateral renal artery stenosis hypertension, different from losartan that is prohibited for treatment of bilateral renal artery stenosis hypertension. Targets validation of MT hypotensive mechanism and beneficial effects of MT on uric acid and cognitive function provide new insights for this novel multitarget drug, deserving clinical trial attention.

Iron Oxide Nanoparticles as Promising Antibacterial Agents of New Generation.

Antimicrobial resistance (AMR) is growing into a major public health crisis worldwide. The reducing alternatives to conventional agents starve for novel antimicrobial agents. Due to their unique magnetic properties and excellent biocompatibility, iron oxide nanoparticles (IONPs) are the most preferable nanomaterials in biomedicine, including antibacterial therapy, primarily through reactive oxygen species (ROS) production. IONP characteristics, including their size, shape, surface charge, and superparamagnetism, influence their biodistribution and antibacterial activity. External magnetic fields, foreign metal doping, and surface, size, and shape modification improve the antibacterial effect of IONPs. Despite a few disadvantages, IONPs are expected to be promising antibacterial agents of a new generation.

Single-bundle ACL combined with ALL reconstruction yields comparable outcomes in patients with varied anatomical risk factors for ACL graft failure.

BACKGROUND: Anterior cruciate ligament (ACL) graft failure is influenced by factors such as meniscal tears and tibial plateau slope. Combined anterior cruciate ligament (ACL) and anterolateral ligament (ALL) reconstruction has reduced failure rates; however, its efficacy in high-risk patients remains unclear. This study hypothesized that combined ACL and ALL reconstruction would yield similar clinical outcomes in patients with varying risks of ACL failure. PATIENTS AND METHODS: A total of 76 patients who underwent primary single-bundle ACL reconstruction combined with ALL reconstruction between June 2018 and June 2021 were included. The medial tibial slope (MTS), lateral tibial slope (LTS), and anterior tibial translation (ATT) were measured using magnetic resonance imaging and plain radiography of the knee joint. The meniscal lesions were assessed during surgery. Preoperative clinical assessments and final follow-up were conducted using patient-reported outcome measurements (PROMs), including the International Knee Documentation Committee (IKDC) evaluation, Lysholm knee scoring scale, and Tegner Activity scale. PROMs were collected at least two years postoperatively. RESULTS: The average follow-up was 32.5 ± 7.4 months. There were no significant differences in postoperative IKDC score, Lysholm score, or Tegner activity score between patients with or without medial meniscus injury (p = 0.155, 0.914, and 0.042, respectively), with or without lateral meniscus injury (p = 0.737, 0.569, and 0.942, respectively), medial tibial slope > 12° or ≤ 12° (p = 0.290, 0.496, and 0.988, respectively), or lateral tibial slope > 7.4° or ≤ 7.4° (p = 0.213, 0.625, and 0.922, respectively). No significant correlations were found between anterior tibial translation and postoperative IKDC (R = -0.058, p = 0.365), Lysholm (R = -0.017, p = 0.459), or Tegner activity scores (R = -0.147, p = 0.189). CONCLUSION: Our study demonstrates that single-bundle ACL reconstruction combined with ALL reconstruction provides reliable and comparable clinical outcomes in patients with high-risk factors for ACL graft failure, such as increased tibial slope or meniscal injury. Our results suggest that the indications for ALL reconstruction may be expanded to include patients with a high tibial slope or meniscal injury, because these factors have been shown to contribute to increased rotational instability and high rates of ACL graft failure. Future prospective randomized controlled trials with large patient cohorts and long follow-up periods are needed to validate these findings and establish clear guidelines for patient selection and surgical decision-making. LEVEL OF EVIDENCE: Level 3.

Effect of nocturia in patients with different severity of obstructive sleep apnea on polysomnography: A retrospective observational study.

Objective: Obstructive sleep apnea (OSA) is one of the etiologies of nocturia. We analyzed polysomnography (PSG) results to determine correlated factors related to nocturia in OSA patients with different severity. Methods: Patients with suspected OSA were examined using PSG. They were divided into two groups based on the presence of nocturia. Nocturia was defined as a patient who needed to void at least once. Apnea-hypopnea index (AHI) was employed to classify patients according to degrees of severity: AHI<5 events/h, 5 events/h≤AHI<15 events/h, 15 events/h≤AHI<30 events/h, and AHI≥30 events/h, defined as normal, mild OSA, moderate OSA, and severe OSA, respectively. Demographic variables, PSG parameters, International Prostate Symptom Scores (IPSSs), and quality of life scores due to urinary symptoms were analyzed. Results: In total 140 patients, 114 patients had OSA (48 had mild OSA; 34 had moderate OSA; and 32 had severe OSA) and 107 patients had nocturia. The total IPSS was significantly higher in nocturia patients in all groups except the group of severe OSA patients. With the increasing severity of OSA, more correlated factors related to nocturia were determined. In mild OSA patients, nocturia related to increased age (p=0.025), minimum arterial blood oxygenation saturation (p=0.046), and decreased AHI of non-rapid eye movement (p=0.047), AHI of total sleep time (p=0.010), and desaturation index (p=0.012). In moderate OSA patients, nocturia related to increased age (p<0.001), awake time (p=0.025), stage 1 sleep (p=0.033), and sleep latency (p=0.033), and decreased height (p=0.044), weight (p=0.025), and sleep efficiency (p=0.003). In severe OSA patients, nocturia related to increased weight (p=0.011), body mass index (p=0.009), awake time (p=0.008), stage 1 sleep (p=0.040), arousal number (p=0.030), arousal index (p=0.013), periodic limb movement number (p=0.013), and periodic limb movement index (p=0.004), and decreased baseline arterial blood oxygenation saturation (p=0.046). Conclusion: Our study revealed that there were more correlated factors related to nocturia with increasing severity of OSA. This study helps in clinical education and treatment for OSA patients with different severity.

Fastball Quality After Ulnar Collateral Ligament Reconstruction in Major League Baseball Pitchers.

BACKGROUND: The ulnar collateral ligament (UCL) is essential for elbow stability during pitching. In professional baseball, the fastball (FB) is the most commonly used pitch, making postrecovery FB performance after UCL reconstruction (UCLR) a crucial aspect to consider. HYPOTHESES: (1) Pitchers undergoing UCLR would show no significant changes in performance metrics compared with nonoperated pitchers with similar FB velocity and spin rate, and (2) no significant variance would be found in these metrics within the operated pitchers concerning their preinjury anthropometric characteristics and pitching performance metrics. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: The study included 91 Major League Baseball (MLB) pitchers who underwent primary UCLR between January 1, 2015, and December 31, 2021. A matched 1:1 control group of MLB pitchers without UCLR injuries was established. Publicly available pitch metrics and anthropometric data were compared between the study and control groups. RESULTS: Disparities in several performance metrics emerged during the first postreturn year (PRY1), including FB use percentage (P = .029), fielder independent pitching (FIP) (P = .021), and standardized FB runs above average per 100 pitches (wFB/C) (P < .001). Subgroup analysis within the UCLR group revealed a negative correlation between presurgery mean FB velocity and its subsequent change (P < .001) and a positive correlation with changes in FIP (P = .025) from the index year to PRY1. A negative correlation was observed between FB use percentage in the index year and its change by PRY1 (P = .002). By the second postreturn year, no significant differences were found in these performance metrics. No factors were significantly related to prolonged recovery time. CONCLUSION: Although FB velocity and spin rate remained consistent, significant differences were observed in FB use percentage, FIP, and wFB/C in PRY1. However, by second postreturn year, these differences were no longer significant. No specific risk factors were identified concerning prolonged recovery time between pre-UCLR FB pitching metrics and the physical anthropometric data. These results suggest that although the short-term postsurgery period may affect more specialized pitching metrics, the basic pitching performance metrics, as hypothesized, remain largely unaffected by UCLR.

Double-bundle ACL combined with ALL reconstruction for patients at high risk of ACL failure: clinical and radiological results.

BACKGROUND: We investigated whether double-bundle (DB) anterior cruciate ligament (ACL) reconstruction (ACLR) combined with anterolateral ligament reconstruction (ALLR) improved clinical and radiological outcomes in patients at high risk of ACL failure. The primary outcome was graft failure, and secondary outcomes included knee stability and patient-reported outcome measures (PROMs). PATIENTS AND METHODS: Fifty-two patients who underwent DB ACLR combined with ALLR were included in this retrospective cohort study. Preoperative risk factors, including femorotibial angle (FTA), lateral tibial slope (LTS), medial tibial slope (MTS), and meniscal tears, were assessed using X-ray and magnetic resonance imaging (MRI). The grade of post-operative pivot shift, Lysholm score, and Tegner activity score were used to assess clinical outcomes. The minimum follow up duration was 2 years. RESULTS: The cohort (mean age, 26.1 ± 9.4 years; 51.9% male) had a mean follow-up duration of 28.9 ± 3.4 months. Preoperatively, 57.8% had lateral meniscus (LM) tears, and 61.0% had a grade 2-3 pivot shift. Postoperatively, no graft failures or revision cases occurred during follow-up. Approximately 90.4% of the patients exhibited a negative pivot shift (p < 0.001), with Lysholm and Tegner activity scores of 92.5 ± 6.1 and 5.1 ± 2.0. The medial meniscus (MM) tear group had a significantly smaller FTA than the intact group (p = 0.043). No significant differences in PROMs were found between the LM tear and intact LM groups or between the high and low MTS or LTS groups (p = n.s.). CONCLUSION: DB ACLR combined with ALLR had satisfactory clinical outcomes in patients at high risk of ACL failure, with no graft failures observed during a mean follow-up duration of 2.4 years. The technique effectively reduced the postoperative pivot shift, regardless of preoperative risk factors. STUDY DESIGN: Level IV, retrospective therapeutic case-series. TRAIL REGISTRATION: ethical approval number, 202300134B0; ethical committee, the Institutional Review Board of Chang Gung Medical Foundation.

Performance of Microsoft Azure Kinect DK as a tool for estimating human body segment lengths.

The Microsoft Kinect depth sensor, with its built-in software that automatically captures joint coordinates without markers, could be a potential tool for ergonomic studies. This study investigates the performance of Kinect in limb segment lengths using dual-energy X-ray absorptiometry (DXA) as a reference. Healthy children and adults (n = 76) were recruited for limb length measurements by Kinect and DXA. The results showed consistent ratios of arm, forearm, thigh, and leg lengths to height, which were 0.16, 0.14, 0.23, and 0.22 respectively, for both age groups and methods. Kinect exhibited perfect correlation among all limb lengths, indicating fixed proportions assumed by its algorithm. Comparing the two methods, there was a strong correlation (R = 0.850-0.985) and good to excellent agreement (ICC = 0.829-0.977), except for the right leg in adults, where agreement was slightly lower but still moderate (ICC = 0.712). The measurement bias between the methods ranged from - 1.455 to 0.536 cm. In conclusion, Kinect yields outcomes similar to DXA, indicating its potential utility as a tool for ergonomic studies. However, the built-in algorithm of Kinect assumes fixed limb proportions for individuals, which may not be ideal for studies focusing on investigating limb discrepancies or anatomical differences.

The Oncolytic Avian Reovirus p17 Protein Inhibits Invadopodia Formation in Murine Melanoma Cancer Cells by Suppressing the FAK/Src Pathway and the Formation of theTKs5/NCK1 Complex.

To explore whether the p17 protein of oncolytic avian reovirus (ARV) mediates cell migration and invadopodia formation, we applied several molecular biological approaches for studying the involved cellular factors and signal pathways. We found that ARV p17 activates the p53/phosphatase and tensin homolog (PTEN) pathway to suppress the focal adhesion kinase (FAK)/Src signaling and downstream signal molecules, thus inhibiting cell migration and the formation of invadopodia in murine melanoma cancer cell line (B16-F10). Importantly, p17-induced formation of invadopodia could be reversed in cells transfected with the mutant PTENC124A. p17 protein was found to significantly reduce the expression levels of tyrosine kinase substrate 5 (TKs5), Rab40b, non-catalytic region of tyrosine kinase adaptor protein 1 (NCK1), and matrix metalloproteinases (MMP9), suggesting that TKs5 and Rab40b were transcriptionally downregulated by p17. Furthermore, we found that p17 suppresses the formation of the TKs5/NCK1 complex. Coexpression of TKs5 and Rab40b in B16-F10 cancer cells reversed p17-modulated suppression of the formation of invadopodia. This work provides new insights into p17-modulated suppression of invadopodia formation by activating the p53/PTEN pathway, suppressing the FAK/Src pathway, and inhibiting the formation of the TKs5/NCK1 complex.

Investigating the postoperative soft tissue changes in different vertical facial divergent patients with mandibular prognathism.

Background/purpose: The extent of three-dimensional soft tissue changes in patients with varied facial skeletal patterns following mandibular setback surgery remains unclear. In this study, we aimed to investigate the postoperative changes in soft tissue chin thickness among mandibular prognathism patients, focusing on those presenting different divergence patterns, such as hyperdivergent and normodivergent patients. Materials and methods: Cone-beam computed tomography images were obtained from 56 skeletal Class III patients who underwent only mandibular setback. Based on vertical craniofacial skeletal relationship, patients were divided into normodivergent group (27°37°) group. The three-dimensional displacements of Infradentale (Id), B point (B), and Pogonion (Pog), the soft tissue thickness of Id-Li (Labrale inferius), B-B' (soft tissue B point), and Pog-Pog' (soft tissue Pog point) were measured. Factors influencing the change in soft tissue thickness were investigated. Results: Preoperative B-B' and Pog-Pog' thickness were significantly thinner in the hyperdivergent group than normodivergent group. Postoperative changes in B-B' and Pog-Pog' thickness were significantly larger in the hyperdivergent group than normodivergent group. A significant correlation was found between soft tissue thickness change (B-B' and Pog-Pog') and the preoperative soft tissue thickness and superior movement (B and Pog). Conclusion: Hyperdivergent patients with skeletal class III have thinner preoperative soft tissue thickness (B-B' and Pog-Pog') than normodivergent patients in the preoperation. Postoperative changes in B-B' and Pog-Pog' thickness were significantly larger in the hyperdivergent group than normodivergent group. Postoperative superior movement of B and Pog correlated with postoperative change of soft tissue thickness.

Invasive Listeriosis in End-Stage Kidney Disease (ESKD) Patients Receiving Long-Term Dialysis: A 21-Year Case Series.

Background: Listeriosis is caused by the facultative anaerobic bacterium Listeria monocytogenes. Infection from Listeria-contaminated food or water is the main etiology. If Listeria travels outside the intestines, it can cause invasive listeriosis, such as sepsis, meningitis, and meningoencephalitis. Invasive illness is especially dangerous for pregnant women and their newborns, elderly people, and people with compromised immune systems or medical conditions such as end-stage kidney disease (ESKD) patients receiving long-term dialysis. Purpose: Describe the manifestations and hospital outcomes of invasive listeriosis and identify the risk factors for in-hospital and one-year mortality in ESKD patients receiving long-term dialysis. Patients and Methods: This retrospective observational study examined hospitalized patient records at a Taiwanese tertiary medical center from August 1, 2000, to August 31, 2021. ESKD patients on chronic dialysis were identified with invasive listeriosis by blood culture and discharge diagnosis. Over 21 years, we accurately recorded 26 cases. Results: ESKD patients on chronic dialysis with invasive listeriosis have a poor prognosis. Only 53.8% of chronic dialysis patients with invasive listeriosis survived their first hospital episode. 42.3% of hospitalized ESKD patients with invasive listeriosis survived one year later. In univariate analysis, shock, tachypnea (RR ≥ 22), respiratory failure, qSOFA score ≥ 2, and lower initial platelet count were linked to greater in-hospital mortality rates. Conclusion: ESKD patients with invasive listeriosis have a grave prognosis. Our research reveals that an early blood sample for a bacterial culture may identify invasive listeriosis in chronic dialysis patients with fever, nausea or vomiting, confusion, and respiratory distress. This study is the first to identify a lower platelet count and qSOFA score ≥ 2 as markers of high-risk invasive listeriosis in ESKD patients.

STAT5B Suppresses Ferroptosis by Promoting DCAF13 Transcription to Regulate p53/xCT Pathway to Promote Mantle Cell Lymphoma Progression.

Objective: The purpose of this study was to analyze the mechanism by which STAT5B inhibits ferroptosis in mantle cell lymphoma (MCL) by promoting DCAF13 transcriptional regulation of p53/xCT pathway. Methods: The correlations between STAT5B, DCAF13 and ferroptosis in MCL were analyzed using Gene Expression Profiling Interactive Analysis (GEPIA, http://gepia.cancer-pku.cn/index.html). The expression levels and pairwise correlations of STAT5B, DCAF13, p53 and xCT in MCL patients were detected, respectively. STAT5B was silenced to confirm their criticality in MCL ferroptosis. the effects of blocking necrosis, apoptosis and ferroptosis on the anti-MCL effects of STAT5B were examined. Cells with STAT5B overexpression and/or DCAF13 silencing were constructed to confirm the involvement of DCAF13 in the STAT5B-regulated p53/xCT pathway. The regulation of p53 ubiquitination was confirmed by DCAF13 overexpression and MG132. The effects of silencing DCAF13 and MG132 on STAT5B overexpression on MCL was clarified by a tumor-bearing nude mouse model. Results: DCAF13 was overexpressed in MCL and positively correlated with STAT5B, negatively correlated with p53, and positively correlated with xCT. Inhibition of ferroptosis alleviated the inhibitory effects of siSTAT5B on MCL, while inhibition of necrosis and apoptosis had few effects. Silencing of DCAF13 led to the blocking of STAT5B regulation of p53/xCT and ferroptosis. The changes in DCAF13 and the addition of MG132 did not have statistically significant effects on p53 mRNA. Elevation of DCAF13 resulted in downregulation of p53 protein levels, and this inhibition was reversed by MG132. In animal models, the promotion of MCL and the inhibition of ferroptosis by STAT5B. Silencing of DCAF13 blocked STAT5B inhibition of p53 and induction of xCT, GPX4, and GSH. Conclusion: STAT5B suppresses ferroptosis by promoting DCAF13 transcription to regulate p53/xCT pathway to promote MCL progression.

α-Ketoglutarate plays an inflammatory inhibitory role by regulating scavenger receptor class a expression through N6-methyladenine methylation during sepsis.

Sepsis arises from an uncontrolled inflammatory response triggered by infection or stress, accompanied by alteration in cellular energy metabolism, and a strong correlation exists between these factors. Alpha-ketoglutarate (α-KG), an intermediate product of the TCA cycle, has the potential to modulate the inflammatory response and is considered a crucial link between energy metabolism and inflammation. The scavenger receptor (SR-A5), a significant pattern recognition receptor, assumes a vital function in anti-inflammatory reactions. In the current investigation, we have successfully illustrated the ability of α-KG to mitigate inflammatory factors in the serum of septic mice and ameliorate tissue damage. Additionally, α-KG has been shown to modulate metabolic reprogramming and macrophage polarization. Moreover, our findings indicate that the regulatory influence of α-KG on sepsis is mediated through SR-A5. We also elucidated the mechanism by which α-KG regulates SR-A5 expression and found that α-KG reduced the N6-methyladenosine level of macrophages by up-regulating the m6A demethylase ALKBH5. α-KG plays a crucial role in inhibiting inflammation by regulating SR-A5 expression through m6A demethylation during sepsis. The outcomes of this research provide valuable insights into the relationship between energy metabolism and inflammation regulation, as well as the underlying molecular regulatory mechanism.

Discovery of MT-1207: A Novel, Potent Multitarget Inhibitor as a Promising Clinical Candidate for the Treatment of Hypertension.

Herein, a series of novel arylpiperazine (piperidine) derivatives were designed, synthesized, and evaluated for mechanisms of action through in vitro and in vivo studies. The most promising compound, II-13 (later named as MT-1207), is a potent α1 and 5-HT2A receptor antagonist with remarkable IC50 in the picomolar level. Importantly, in the in vivo assay, II-13 achieved an effective blood pressure (BP) reduction in the 2K2C rat model without damaging renal function. Compound II-13, with its significant advantages in terms of pharmacological effects, pharmacokinetic parameters, and a large safety window, was extensively investigated. Moreover, data also showed that compound II-13 had fewer side effects in a postural BP assay and could prevent the onset of postural hypotension. Together, these results suggested that compound II-13 is a highly potent antihypertensive drug candidate with multitarget mechanisms of action in preclinical models. Currently, MT-1207 is in phase II hypertensive clinical trials in China.

Predictive value of preoperative routine examination for the prognosis of patients with pT2N0M0 or pT3N0M0 colorectal cancer.

BACKGROUND: In recent years, the incidence of colorectal cancer (CRC) has been increasing. With the popularization of endoscopic technology, a number of early CRC has been diagnosed. However, despite current treatment methods, some patients with early CRC still experience postoperative recurrence and metastasis. AIM: To search for indicators associated with early CRC recurrence and metastasis to identify high-risk populations. METHODS: A total of 513 patients with pT2N0M0 or pT3N0M0 CRC were retrospectively enrolled in this study. Results of blood routine test, liver and kidney function tests and tumor markers were collected before surgery. Patients were followed up through disease-specific database and telephone interviews. Tumor recurrence, metastasis or death were used as the end point of study to find the risk factors and predictive value related to early CRC recurrence and metastasis. RESULTS: We comprehensively compared the predictive value of preoperative blood routine, blood biochemistry and tumor markers for disease-free survival (DFS) and overall survival (OS) of CRC. Cox multivariate analysis demonstrated that low platelet count was significantly associated with poor DFS [hazard ratio (HR) = 0.995, 95% confidence interval (CI): 0.991-0.999, P = 0.015], while serum carcinoembryonic antigen (CEA) level (HR = 1.008, 95%CI: 1.001-1.016, P = 0.027) and serum total cholesterol level (HR = 1.538, 95%CI: 1.026-2.305, P = 0.037) were independent risk factors for OS. The cutoff value of serum CEA level for predicting OS was 2.74 ng/mL. Although the OS of CRC patients with serum CEA higher than the cutoff value was worse than those with lower CEA level, the difference between the two groups was not statistically significant (P = 0.075). CONCLUSION: For patients with T2N0M0 or T3N0M0 CRC, preoperative platelet count was a protective factor for DFS, while serum CEA level was an independent risk factor for OS. Given that these measures are easier to detect and more acceptable to patients, they may have broader applications.

Development of Carbon Black Coating on TPU Elastic Powder for Selective Laser Sintering.

Increased usage of selective laser sintering (SLS) for the production of end-use functional components has generated a requirement of developing new materials and process improvements to improve the applicability of this technique. This article discusses a novel process wherein carbon black was applied to the surface of TPU powder to reduce the laser reflectivity during the SLS process. The printing was carried out with a preheating temperature of 75 °C, laser energy density of 0.028 J/mm2, incorporating a 0.4 wt % addition of carbon black to the TPU powder, and controlling the powder layer thickness at 125 µm. The mixed powder, after printing, shows a reflectivity of 13.81%, accompanied by the highest average density of 1.09 g/cm3, hardness of 78 A, tensile strength of 7.9 MPa, and elongation at break was 364.9%. Compared to commercial TPU powder, which lacks the carbon black coating, the reflectance decreased by 1.78%, mechanical properties improved by 33.9%, and there was a notable reduction in the porosity of the sintered product.

Application and challenge of pancreatic organoids in therapeutic research.

The in-vivo non-human primate animal and in-vitro cell disease models play a crucial part in the study of the mechanisms underlying the occurrence and development of pancreatic diseases, but with increasingly prominent limitations with in-depth research. Organoids derived from human pluripotent and adult stem cells resemble human in-vivo organs in their cellular composition, spatial tissue structure and physiological function, making them as an advantageous research tool. Up until now, numerous human organoids, including pancreas, have been effectively developed, demonstrating significant potential for research in organ development, disease modeling, drug screening, and regenerative medicine. However, different from intestine, liver and other organs, the pancreas is the only special organ in the human body, consisting of an exocrine gland and an endocrine gland. Thus, the development of pancreatic organoid technology faces greater challenges, and how to construct a composite pancreatic organoid with exocrine and endocrine gland is still difficult in current research. By reviewing the fundamental architecture and physiological role of the human pancreas, along with the swiftly developing domain of pancreatic organoids, we summarize the method and characteristics of human pancreatic organoids, and its application in modeling pancreatic diseases, as a platform for individualized drug screening and in regenerative medicine study. As the first comprehensive review that focus on the pharmacological study of human pancreatic organoid, the review hopes to help scholars to have a deeper understanding in the study of pancreatic organoid.

The risk of herpes zoster is positively associated with obesity, especially morbid obesity.

This study aimed to investigate the association between obesity and herpes zoster (HZ) occurrence. This study used data covering 2 million people in Taiwan in 2000, which were obtained from the National Health Insurance Research Database. The cohort study observed aged 20-100 years with obesity from 2000 to 2017 (tracking to 2018). Obesity was indicated by the presence of two or more outpatient diagnoses or at least one admission record. And, obesity was categorized into non-morbid obesity and morbid obesity. Patients with HZ before the index date were excluded. The obesity cohort and control cohort were matched 1:1 according to age, sex, comorbidities, and index year. There were 18,855 patients in both the obesity and control cohorts. The obesity cohort [adjusted hazard ratio (aHR) 1.09] had a higher risk of HZ than the control cohort. Further analysis, the morbid obesity group (aHR 1.47), had a significantly higher risk of HZ than the non-morbid obesity group. Among the patients without any comorbidities, the patients with obesity had a significantly higher risk of developing HZ than the patients without obesity (aHR 1.18). Obese patients are at a higher risk of HZ development, especially in the patients with morbid obesity. Weight reduction is critical for preventing the onset of chronic diseases and decreasing the risk of HZ in patients with obesity.

An optimized ligation-mediated PCR method for chromosome walking and fusion gene chromosomal breakpoints identification.

Molecular techniques that recover unknown sequences next to a known sequence region have been widely applied in various molecular studies, such as chromosome walking, identification of the insertion site of transposon mutagenesis, fusion gene partner, and chromosomal breakpoints, as well as targeted sequencing library preparation. Although various techniques have been introduced for efficiency enhancement, searching for relevant single molecular event present in a large-sized genome remains challenging. Here, the optimized ligation-mediated polymerase chain reaction (PCR) method was developed and successfully identified chromosomal breakpoints far away from the exon of the new exon junction without the need for nested PCR. In addition to recovering unknown sequences next to a known sequence region, the high efficiency of the method could also improve the performance of targeted  next-generation sequencing (NGS).

[Three-dimensional finite element analysis of lumbar disc herniation under different body positions].

OBJECTIVE: To campare biomechanical effects of different postural compression techniques on three-dimensional model of lumbar disc herniation (LDH) by finite element analysis. METHODS: Lumbar CT image of a 48-year-old female patient with LDH (heighted 163 cm, weighted 53 kg) was collected. Mimics 20.0, Geomagic Studio, Solidwords and other software were used to establish three-dimensional finite element model of LDH on L4,5 segments. Compression techniques under horizontal position, 30° forward bending and 10° backward extension were simulated respectively. After applying the pressure, the effects of compression techniques under different positions on stress, strain and displacement of various tissues of intervertebral disc and nerve root were observed. RESULTS: L4, 5 segment finite element model was successfully established, and the model was validated. When compression manipulation was performed on the horizontal position, 30° flexion and 10° extension, the annular stress were 0.732, 5.929, 1.286 MPa, the nucleus pulposus stress were 0.190, 1.527, 0.295 MPa, and the annular strain were 0.097, 0.922 and 0.424, the strain sizes of nucleus pulposus were 0.153, 1.222 and 0.282, respectively. The overall displacement distance of intervertebral disc on Y direction were -3.707, -18.990, -4.171 mm, and displacement distance of nerve root on Y direction were +7.836, +5.341, +3.859 mm, respectively. The relative displacement distances of nerve root and intervertebral disc on Y direction were 11.543, 24.331 and 8.030 mm, respectively. CONCLUSION: Compression manipulation could make herniated intervertebral disc produce contraction and retraction trend, by increasing the distance between herniated intervertebral disc and nerve root, to reduce symptoms of nerve compression, to achieve purpose of treatment for patients with LDH, in which the compression manipulation is more effective when the forward flexion is 30°.

Drosophila Models Uncover Substrate Channeling Effects on Phospholipids and Sphingolipids in Peroxisomal Biogenesis Disorders.

Peroxisomal Biogenesis Disorders Zellweger Spectrum (PBD-ZSD) disorders are a group of autosomal recessive defects in peroxisome formation that produce a multi-systemic disease presenting at birth or in childhood. Well documented clinical biomarkers such as elevated very long chain fatty acids (VLCFA) are key biochemical diagnostic findings in these conditions. Additional, secondary biochemical alterations such as elevated very long chain lysophosphatidylcholines are allowing newborn screening for peroxisomal disease. In addition, a more widespread impact on metabolism and lipids is increasingly being documented by metabolomic and lipidomic studies. Here we utilize Drosophila models of pex2 and pex16 as well as human plasma from individuals with PEX1 mutations. We identify phospholipid abnormalities in Drosophila larvae and brain characterized by differences in the quantities of phosphatidylcholine (PC) and phosphatidylethanolamines (PE) with long chain lengths and reduced levels of intermediate chain lengths. For diacylglycerol (DAG) the precursor of PE and PC through the Kennedy pathway, the intermediate chain lengths are increased suggesting an imbalance between DAGs and PE and PC that suggests the two acyl chain pools are not in equilibrium. Altered acyl chain lengths are also observed in PE ceramides in the fly models. Interestingly, plasma from human subjects exhibit phospholipid alterations similar to the fly model. Moreover, human plasma shows reduced levels of sphingomyelin with 18 and 22 carbon lengths but normal levels of C24. Our results suggest that peroxisomal biogenesis defects alter shuttling of the acyl chains of multiple phospholipid and ceramide lipid classes, whereas DAG species with intermediate fatty acids are more abundant. These data suggest an imbalance between de novo synthesis of PC and PE through the Kennedy pathway and remodeling of existing PC and PE through the Lands cycle. This imbalance is likely due to overabundance of very long and long acyl chains in PBD and a subsequent imbalance due to substrate channeling effects. Given the fundamental role of phospholipid and sphingolipids in nervous system functions, these observations suggest PBD-ZSD are diseases characterized by widespread cell membrane lipid abnormalities.