Real-world Effectiveness and Tolerability of Interferon-free Direct-acting Antiviral for 15,849 Patients with Chronic Hepatitis C: A Multinational Cohort Study.

Background and Aims: As practice patterns and hepatitis C virus (HCV) genotypes (GT) vary geographically, a global real-world study from both East and West covering all GTs can help inform practice policy toward the 2030 HCV elimination goal. This study aimed to assess the effectiveness and tolerability of DAA treatment in routine clinical practice in a multinational cohort for patients infected with all HCV GTs, focusing on GT3 and GT6. Methods: We analyzed the sustained virological response (SVR12) of 15,849 chronic hepatitis C patients from 39 Real-World Evidence from the Asia Liver Consortium for HCV clinical sites in Asia Pacific, North America, and Europe between 07/01/2014-07/01/2021. Results: The mean age was 62±13 years, with 49.6% male. The demographic breakdown was 91.1% Asian (52.9% Japanese, 25.7% Chinese/Taiwanese, 5.4% Korean, 3.3% Malaysian, and 2.9% Vietnamese), 6.4% White, 1.3% Hispanic/Latino, and 1% Black/African-American. Additionally, 34.8% had cirrhosis, 8.6% had hepatocellular carcinoma (HCC), and 24.9% were treatment-experienced (20.7% with interferon, 4.3% with direct-acting antivirals). The largest group was GT1 (10,246 [64.6%]), followed by GT2 (3,686 [23.2%]), GT3 (1,151 [7.2%]), GT6 (457 [2.8%]), GT4 (47 [0.3%]), GT5 (1 [0.006%]), and untyped GTs (261 [1.6%]). The overall SVR12 was 96.9%, with rates over 95% for GT1/2/3/6 but 91.5% for GT4. SVR12 for GT3 was 95.1% overall, 98.2% for GT3a, and 94.0% for GT3b. SVR12 was 98.3% overall for GT6, lower for patients with cirrhosis and treatment-experienced (TE) (93.8%) but ≥97.5% for treatment-naive patients regardless of cirrhosis status. On multivariable analysis, advanced age, prior treatment failure, cirrhosis, active HCC, and GT3/4 were independent predictors of lower SVR12, while being Asian was a significant predictor of achieving SVR12. Conclusions: In this diverse multinational real-world cohort of patients with various GTs, the overall cure rate was 96.9%, despite large numbers of patients with cirrhosis, HCC, TE, and GT3/6. SVR12 for GT3/6 with cirrhosis and TE was lower but still excellent (>91%).

Lack of mismatch repair enhances resistance to methylating agents for cells deficient in oxidative demethylation.

The human alkylation B (AlkB) homologs, ALKBH2 and ALKBH3, respond to methylation damage to maintain genomic integrity and cellular viability. Both ALKBH2 and ALKBH3 are direct reversal repair enzymes that remove 1-methyladenine (1meA) and 3-methylcytosine (3meC) lesions commonly generated by alkylating chemotherapeutic agents. Thus, the existence of deficiencies in ALKBH proteins can be exploited in synergy with chemotherapy. In this study, we investigated possible interactions between ALKBH2 and ALKBH3 with other proteins that could alter damage response and discovered an interaction with the mismatch repair (MMR) system. To test whether the lack of active MMR impacts ALKBH2 and/or ALKBH3 response to methylating agents, we generated cells deficient in ALKBH2, ALKBH3, or both in addition to Mlh homolog 1 (MLH1), another MMR protein. We found that MLH1koALKBH3ko cells showed enhanced resistance toward SN1- and SN2-type methylating agents, whereas MLH1koALKBH2ko cells were only resistant to SN1-type methylating agents. Concomitant loss of ALKBH2 and ALKBH3 (ALKBH2ko3ko) rendered cells sensitive to SN1- and SN2-agents, but the additional loss of MLH1 enhanced resistance to both types of damage. We also showed that ALKBH2ko3ko cells have an ATR-dependent arrest at the G2/M checkpoint, increased apoptotic signaling, and replication fork stress in response to methylation. However, these responses were not observed with the loss of functional MLH1 in MLH1koALKBH2ko3ko cells. Finally, in MLH1koALKBH2ko3ko cells, we observed elevated mutant frequency in untreated and temozolomide treated cells. These results suggest that obtaining a more accurate prognosis of chemotherapeutic outcome requires information on the functionality of ALKBH2, ALKBH3, and MLH1.

Two-year carcinogenicity study of a novel plasticizer, bis(2-ethylhexyl) cyclohexane-1,4-dicarboxylate (Eco-DEHCH), by oral diet in Han Wistar rats.

Plasticizers are necessary for the usability of various products, including food contact materials. Exposure to plasticizers is most commonly made through the oral route. Several plasticizers have been reported to have adverse effects on humans and the environment. Thus, the present study aimed to determine the long-term toxicity and carcinogenicity of a novel plasticizer called bis(2-ethylhexyl) cyclohexane-1,4-dicarboxylate (Eco-DEHCH), which is an ecofriendly and biologically less harmful replacer. Groups of 50 male and 50 female Han Wistar rats were fed Eco-DEHCH at daily doses of 1,600, 5,000, or 16,000 ppm in their diet for at least 104 weeks. The rats were regularly monitored for mortality, clinical signs, body weight, food consumption, food efficiency, and perceivable mass. All animals were subjected to complete necropsy and histopathological examination. The results indicate that the rats well tolerated chronic exposure to Eco-DEHCH at highest daily doses of 16,000 ppm, with was equivalent to 805.1 mg/kg/day in males and 1060.6 mg/kg/day in females and did not show signs of toxicity or carcinogenicity. In conclusion, Eco-DEHCH could be a safe and promising alternative plasticizer.

Sex and ethnic disparities in hepatitis B evaluation and treatment across the world.

BACKGROUND & AIMS: Oral antiviral therapy with nucleos(t)ide analogues (NAs) for chronic hepatitis B (CHB) is well-tolerated and lifesaving, but real-world data on utilization are limited. We examined rates of evaluation and treatment in patients from the REAL-B consortium. METHODS: This was a cross-sectional study nested within our retrospective multinational clinical consortium (2000-2021). We determined the proportions of patients receiving adequate evaluation, meeting AASLD treatment criteria, and initiating treatment at any time during the study period. We also identified factors associated with receiving adequate evaluation and treatment using multivariable logistic regression analyses. RESULTS: We analyzed 12,566 adult treatment-naïve patients with CHB from 25 centers in 9 countries (mean age 47.1 years, 41.7% female, 96.1% Asian, 49.6% Western region, 8.7% cirrhosis). Overall, 73.3% (9,206 patients) received adequate evaluation. Among the adequately evaluated, 32.6% (3,001 patients) were treatment eligible by AASLD criteria, 83.3% (2,500 patients) of whom were initiated on NAs, with consistent findings in analyses using EASL criteria. On multivariable logistic regression adjusting for age, sex, cirrhosis, and ethnicity plus region, female sex was associated with adequate evaluation (adjusted odds ratio [aOR] 1.13, p = 0.004), but female treatment-eligible patients were about 50% less likely to initiate NAs (aOR 0.54, p <0.001). Additionally, the lowest evaluation and treatment rates were among Asian patients from the West, but no difference was observed between non-Asian patients and Asian patients from the East. Asian patients from the West (vs. East) were about 40-50% less likely to undergo adequate evaluation (aOR 0.60) and initiate NAs (aOR 0.54) (both p <0.001). CONCLUSIONS: Evaluation and treatment rates were suboptimal for patients with CHB in both the East and West, with significant sex and ethnic disparities. Improved linkage to care with linguistically competent and culturally sensitive approaches is needed. IMPACT AND IMPLICATIONS: Significant sex and ethnic disparities exist in hepatitis B evaluation and treatment, with female treatment-eligible patients about 50% less likely to receive antiviral treatment and Asian patients from Western regions also about 50% less likely to receive adequate evaluation or treatment compared to Asians from the East (there was no significant difference between Asian patients from the East and non-Asian patients). Improved linkage to care with linguistically competent and culturally sensitive approaches is needed.

Factors associated with long head of the biceps tendon tear severity and predictive insights for grade II tears in rotator cuff surgery.

BACKGROUND: In rotator cuff repair, the long head of the biceps tendon (LHB) is commonly used as graft material. However, factors influencing LHB tear severity are poorly understood, and predicting grade II LHB tears is challenging. This study aimed to identify these factors preoperatively. METHODS: The demographics, medical parameters, and pain severity of 750 patients who underwent arthroscopic surgery from January 2010 to February 2021 were evaluated to determine the factors associated with LHB tear severity and grade II tears. Both overall and largeto-massive rotator cuff tear (RCT) cohorts underwent ordinal and binary logistic regression analyses. Predictive accuracy for grade II LHB tears was determined using the area under the receiver operating characteristic curve (AUC). RESULTS: In the overall cohort, high-sensitivity C-reactive protein (hs-CRP) >1 mg/L (P<0.001), subscapularis tear (P<0.001), hypothyroidism (P=0.031), and the tangent sign (P=0.003) were significantly associated with LHB tear severity, and hs-CRP>1 mg/L, subscapularis tear, and Patte retraction degree were significantly associated with grade II LHB tears (P<0.001). In the large-to-massive RCT cohort, hs-CRP>1 mg/L, hypertension, and age ≥50 years (P<0.05) were significantly associated with LHB tear severity, and hs-CRP>1 mg/L (P<0.001) and hypertension (P=0.026) were significantly associated with grade II LHB tears. In both cohorts, hs-CRP >1 mg/L demonstrated good predictive accuracy for grade II LHB tears (AUCs: 0.72 and 0.70). CONCLUSIONS: Serum hs-CRP >1 mg/L is associated with LHB tear severity and serves as a reliable predictor of grade II LHB tears, facilitating preoperative assessment of the LHB as potential graft material in arthroscopic rotator cuff repair. Level of evidence: III.

Cellular senescence is associated with the spatial evolution toward a higher metastatic phenotype in colorectal cancer.

In this study, we explore the dynamic process of colorectal cancer progression, emphasizing the evolution toward a more metastatic phenotype. The term "evolution" as used in this study specifically denotes the phenotypic transition toward a higher metastatic potency from well-formed glandular structures to collective invasion, ultimately resulting in the development of cancer cell buddings at the invasive front. Our findings highlight the spatial correlation of this evolution with tumor cell senescence, revealing distinct types of senescent tumor cells (types I and II) that play different roles in the overall cancer progression. Type I senescent tumor cells (p16INK4A+/CXCL12+/LAMC2-/MMP7-) are identified in the collective invasion region, whereas type II senescent tumor cells (p16INK4A+/CXCL12+/LAMC2+/MMP7+), representing the final evolved form, are prominently located in the partial-EMT region. Importantly, type II senescent tumor cells associate with local invasion and lymph node metastasis in colorectal cancer, potentially affecting patient prognosis.

CDK4/6 inhibitors induce breast cancer senescence with enhanced anti-tumor immunogenic properties compared with DNA-damaging agents.

Since therapy-induced senescence (TIS) can either support or inhibit cancer progression, identifying which types of chemotherapeutic agents can produce the strongest anti-tumor TIS is an important issue. Here, cyclin-dependent kinase4/6 inhibitors (CDK4/6i)-induced senescence was compared to the TIS induced by conventional DNA-damaging agents. Despite both types of agents eliciting a similar degree of senescence, we observed increased expression of the senescence-associated secretory phenotype (SASP) and ligands related to pro-tumor immunity (IL6, CXCL8, TGFß, CD274, and CEACAM1) and angiogenesis (VEGFA) mainly in TIS induced by DNA-damaging agents rather than by CDK4/6i. Additionally, although all agents increased the expression of anti-tumor immunomodulatory proteins related to antigen presentation (MHC-I, B2M) and T cell chemokines (CXCL9, 10, 11), CDK4/6i-induced senescent cells still maintained this expression at a similar or even higher intensity than cells treated with DNA-damaging agents, despite the absence of nuclear factor-kappa-B (NF-κB) and p53 activation. These data suggest that in contrast with DNA-damaging agents, which augment the pro-tumorigenic microenvironment via pro-inflammatory SASP, CDK4/6i can generate TIS only with antitumor immunomodulatory proteins.

Safety and Feasibility of Intradiscal Administration of Matrilin-3-Primed Adipose-Derived Mesenchymal Stromal Cell Spheroids for Chronic Discogenic Low Back Pain: Phase 1 Clinical Trial.

Functionally enhanced mesenchymal stromal cells participate in the repair of intervertebral disc. This study aimed to assess the safety and tolerability of intradiscal administration of matrilin-3-primed adipose-derived stromal cell (ASC) spheroids with hyaluronic acid (HA) in patients with chronic discogenic low back pain (LBP). In this single-arm, open-label phase I clinical trial, eight patients with chronic discogenic LBP were observed over 6 months. Each patient underwent a one-time intradiscal injection of 1 mL of 6.0 × 106 cells/disc combined with HA under real-time fluoroscopic guidance. Safety and feasibility were gauged using Visual Analogue Scale (VAS) pain and Oswestry Disability Index (ODI) scores and magnetic resonance imaging. All participants remained in the trial, with no reported adverse events linked to the procedure or stem cells. A successful outcome-marked by a minimum 2-point improvement in the VAS pain score and a 10-point improvement in ODI score from the start were observed in six participants. Although the modified Pfirrmann grade remained consistent across all participants, radiological improvements were evident in four patients. Specifically, two patients exhibited reduced high-intensity zones while another two demonstrated decreased disc protrusion. In conclusion, the intradiscal application of matrilin-3-primed ASC spheroids with HA is a safe and feasible treatment option for chronic discogenic LBP.

Senescent tumor cells in colorectal cancer are characterized by elevated enzymatic activity of complexes 1 and 2 in oxidative phosphorylation.

BACKGROUND: Cellular senescence is defined as an irreversible cell cycle arrest caused by various internal and external insults. While the metabolic dysfunction of senescent cells in normal tissue is relatively well-established, there is a lack of information regarding the metabolic features of senescent tumor cells. METHODS: Publicly available single-cell RNA-sequencing data from the GSE166555 and GSE178341 datasets were utilized to investigate the metabolic features of senescent tumor cells. To validate the single-cell RNA-sequencing data, we performed senescence-associated ß-galactosidase (SA-ß-Gal) staining to identify senescent tumor cells in fresh frozen colorectal cancer tissue. We also evaluated nicotinamide adenine dinucleotide dehydrogenase-tetrazolium reductase (NADH-TR) and succinate dehydrogenase (SDH) activity using enzyme histochemical methods and compared the staining with SA-ß-Gal staining. MTT assay was performed to reveal the complex 1 activity of the respiratory chain in in-vitro senescence model. RESULTS: Single-cell RNA-sequencing data revealed an upregulation in the activity of complexes 1 and 2 in oxidative phosphorylation, despite overall mitochondrial dysfunction in senescent tumor cells. Both SA-ß-Gal and enzyme histochemical staining using fresh frozen colorectal cancer tissues indicated a high correlation between SA-ß-Gal positivity and NADH-TR/SDH staining positivity. MTT assay showed that senescent colorectal cancer cells exhibit higher absorbance in 600 nm wavelength. CONCLUSIONS: Senescent tumor cells exhibit distinct metabolic features, characterized by upregulation of complexes 1 and 2 in the oxidative phosphorylation pathway. NADH-TR and SDH staining represent efficient methods for detecting senescent tumor cells in colorectal cancer.

Genomic Mutation Profiles of Patients with Acute Myeloid Leukemia in Korea: a Single-Center Experience.

BACKGROUND: The emergence of next-generation sequencing (NGS) is currently leading the diagnosis of acute myeloid leukemia (AML) and its treatment using a more genetic-level approach. The study aimed to find clinical and prognostic correlations with genomic mutation profiles in Korean patients with AML using NGS. METHODS: This retrospective study enrolled a total of 30 patients who were newly diagnosed with AML from February 2021 to October 2022 in Korea. NGS was used to identify the genetic profiles of 40 genes relevant to AML. The clinical and laboratory data of the patients were analyzed with their genomic mutation profiles. RESULTS: NGS revealed at least one mutation in all patients, with a range of one to seven mutations (median of three mutations). Mutations were commonly associated with TET2, CEBPA, RUNX1, FLT3, IDH2, NPM1, and SRSF2 genes. The TET2 mutation correlated with older (77 vs. 72) patients, and the FLT3 mutation was associated with a higher WBC count (33.4 x 109/L vs. 6.4 x 109/L). The RUNX1 mutation correlated with a lower (44.0 x 109/L vs. 65.5 x 109/L) platelet count, and the NPM1 mutation showed a higher number of blasts in peripheral blood (56.5% vs. 13.0%). Among 16 patients who received induction chemotherapy, mutations in SRSF2, ASXL1, PHF6, SF3B1, and PTPN11 were detected only in patients who failed to achieve complete remission (CR). Meanwhile, mutations in NRAS, TP53, IKZF1, DNMT3A, SH2B3, U2AF1, and WT1 were detected in patients who achieved CR. CONCLUSIONS: Clinical and prognostic correlations were observed according to genomic mutation profiles detected by NGS in Korean patients with AML. An NGS study with a larger cohort of patients would be beneficial to establish the significant prognostic impact on patients with AML.

Saving Stabilizing Structure Treatment With Bilateral-Contralateral Decompression for Spinal Stenosis in Degenerative Spondylolisthesis Using Unilateral Biportal Endoscopy.

OBJECTIVE: This study aimed to evaluate the treatment of spinal stenosis with spondylolisthesis using bilateral-contralateral unilateral biportal endoscopic (UBE) decompression to minimize facet joint damage. METHODS: We retrospectively evaluated 42 patients with grade 1 spondylolisthesis who underwent bilateral-contralateral UBE decompression between July 2018 and September 2019. To identify segmental instability, static and dynamic images from preoperative and postoperative procedures and final follow-up radiographs were reviewed. Lateral radiograph slippage ratio, sagittal motion, and facet joint preservation were evaluated. Clinical assessments were conducted using the visual analogue scale (VAS), Oswestry Disability Index (ODI), and modified MacNab criteria. RESULTS: The average final follow-up period was 26.5 ± 1.3 months. The average preoperative slip percentage was 15.70% ± 5.25%, which worsened to 18.80% ± 5.41% at the final follow-up (p < 0.005). The facet joint preservation rate was 95.6% ± 4.1% on the contralateral side. Improvements in the VAS scores (leg pain: from 7.9 ± 2.2 to 3.1 ± 0.7; p < 0.005; back pain: from 7.2 ± 3.0 to 2.8 ± 1.0; p < 0.005) were observed at the final follow-up. The mean preoperative ODI was 26.19 ± 3.42, which improved to 9.6 ± 1.0 (p < 0.005). Thirteen patients exhibited delayed focal segmental instability following decompression. Despite the absence of symptoms or improvement with conservative treatment in the majority of patients with delayed instability, two patients required fusion surgery to address the instability. Additionally, 2 patients developed facet synovial cysts, while 2 experienced spinous process fractures. CONCLUSION: Bilateral decompression with a contralateral UBE approach could be an effective and alternative treatment method to reduce instability in spinal stenosis with grade 1 spondylolisthesis.

A Case of Marrow Fibrosis with Megakaryocytic Hyperplasia after Short-Term use of Granulocyte Colony-Stimulating Factor.

BACKGROUND: Administration of granulocyte colony-stimulating factors G-SCFs can cause diagnostic challenges because of morphologic alteration of hematopoietic cells. METHODS: We experienced a patient who showed distinctive clinical and morphologic findings after short time use of G-CSF. The clinical information and examination results of the morphology of bone marrow (BM) specimen and karyotype were analyzed by reviewing relevant literature. RESULTS: White blood cell (WBC) counts of the patient were unresponsive to G-CSF and marrow fibrosis and megakaryocytic hyperplasia were accompanied with increase of blasts in BM. Presence of malignant clones was confirmed by cytogenetic aberrations of monosomy 7. CONCLUSIONS: We concluded, BM study including cytogenetic analysis should be performed when such clinical findings are encountered and the possibility of hematologic malignancy should be considered.

T/myeloid mixed-phenotype acute leukemia treated with venetoclax and decitabine: A case report.

BACKGROUND: Mixed-phenotype acute leukemia (MPAL) is characterized by acute undifferentiated leukemia with blasts co-expressing myeloid and lymphoid antigens. However, consensus regarding the ideal management strategy for MPAL is yet to be established, owing to its rarity. CASE SUMMARY: A 55-year-old male was diagnosed with T/myeloid MPAL. Vincristine, prednisolone, daunorubicin, and L-asparaginase were administered as induction chemotherapy. Septic shock occurred 10 days after induction, and bone marrow examination following recovery from sepsis revealed refractory disease. Venetoclax and decitabine were administered as chemotherapy-free induction therapy to reduce the infection risk. There were no serious infections, including febrile neutropenia, at the end of the treatment. After receiving two additional cycles of venetoclax/decitabine, the patient underwent haploidentical peripheral blood stem-cell transplantation and achieved complete response (CR) to treatment. CONCLUSION: CR was maintained in a patient with MPAL who underwent haploidentical peripheral blood stem-cell transplantation after additional venetoclax/decitabine cycles.

Protein phosphatase 4 dephosphorylates phosphofructokinase-1 to regulate its enzymatic activity.

Most cancer cells utilize glucose at a high rate to produce energyand precursors for the biosynthesis of macromolecules such as lipids, proteins, and nucleic acids. This phenomenon is called the Warburg effect or aerobic glycolysis- this distinct characteristic is an attractive target for developing anticancer drugs. Here, we found that Phosphofructokinase-1 (PFK-1) is a substrate of the Protein Phosphatase 4 catalytic subunit (PP4C)/PP4 regulatory subunit 1 (PP4R1) complex by using immunoprecipitation and in vitro assay. While manipulation of PP4C/PP4R1 does not have a critical impact on PFK-1 expression, the absence of the PP4C/PP4R1 complex increases PFK-1 activity. Although PP4C depletion or overexpression does not cause a dramatic change in the overall glycolytic rate, PP4R1 depletion induces a considerable increase in both basal and compensatory glycolytic rates, as well as the oxygen consumption rate, indicating oxidative phosphorylation. Collectively, the PP4C/PP4R1 complex regulates PFK-1 activity by reversing its phosphorylation and is a promising candidate for treating glycolytic disorders and cancers. Targeting PP4R1 could be a more efficient and safer strategy to avoid pleiotropic effects than targeting PP4C directly. [BMB Reports 2023; 56(11): 618-623].

Argon and Oxygen Gas Flow Rate Dependency of Sputtering-Based Indium-Gallium-Zinc Oxide Thin-Film Transistors.

Oxygen vacancies are a major factor that controls the electrical characteristics of the amorphous indium-gallium-zinc oxide transistor (a-IGZO TFT). Oxygen vacancies are affected by the composition ratio of the a-IGZO target and the injected oxygen flow rate. In this study, we fabricated three types of a-IGZO TFTs with different oxygen flow rates and then investigated changes in electrical characteristics. Atomic force microscopy (AFM) was performed to analyze the surface morphology of the a-IGZO films according to the oxygen gas rate. Furthermore, X-ray photoelectron spectroscopy (XPS) analysis was performed to confirm changes in oxygen vacancies of a-IGZO films. The optimized a-IGZO TFT has enhanced electrical characteristics such as carrier mobility (µ) of 12.3 cm2/V·s, on/off ratio of 1.25 × 1010 A/A, subthreshold swing (S.S.) of 3.7 V/dec, and turn-on voltage (Vto) of -3 V. As a result, the optimized a-IGZO TFT has improved electrical characteristics with oxygen vacancies having the highest conductivity.

Real-world treatment outcome with protease inhibitor direct-acting antiviral in advanced hepatitis C cirrhosis: a REAL-C study.

INTRODUCTION: Current guidelines discourage the use of direct-acting antiviral (DAA) containing protease-inhibitor (PI) in advanced HCV cirrhosis. We aimed to compare the real-world tolerability of PI vs. non-PI DAA regimens in this population. METHODS: We identified advanced cirrhosis patients treated with DAA from the REAL-C registry. The primary outcome was significant worsening or improvement in CPT or MELD scores following DAA treatment. RESULTS: From the REAL-C registry of 15,837 patients, we included 1077 advanced HCV cirrhosis patients from 27 sites. 42% received PI-based DAA. Compared to non-PI group, the PI group was older, had higher MELD and higher percentage with kidney disease. Inverse probability of treatment weighting (IPTW; matching on age, sex, history of clinical decompensation, MELD, platelet, albumin, Asia site, Asian ethnicity, hypertension, hemoglobin, genotype, liver cancer, ribavirin) was used to balance the two groups. In the IPTW-matched cohorts, the PI and non-PI groups had similar SVR12 (92.9% vs. 90.7%, p = 0.30), similar percentages of significant worsening in CTP or MELD scores at posttreatment week 12 and 24 (23.9% vs. 13.1%, p = 0.07 and 16.5% vs. 14.6%, p = 0.77), and similar frequency of new HCC, decompensating event, and death by posttreatment week 24. In multivariable analysis, PI-based DAA was not associated with significant worsening (adjusted odds ratio = 0.82, 95% CI 0.38-1.77). CONCLUSION: Tolerability and treatment outcomes were not significantly different in advanced HCV cirrhosis treated with PI-based (vs. non-PI) DAA up to CTP-B or MELD score of 15. Safety of PI-based DAA in those with CTP-C or MELD beyond 15 awaits further data.

Recent advances in endocrine organoids for therapeutic application.

The endocrine system, consisting of the hypothalamus, pituitary, endocrine glands, and hormones, plays a critical role in hormone metabolic interactions. The complexity of the endocrine system is a significant obstacle to understanding and treating endocrine disorders. Notably, advances in endocrine organoid generation allow a deeper understanding of the endocrine system by providing better comprehension of molecular mechanisms of pathogenesis. Here, we highlight recent advances in endocrine organoids for a wide range of therapeutic applications, from cell transplantation therapy to drug toxicity screening, combined with development in stem cell differentiation and gene editing technologies. In particular, we provide insights into the transplantation of endocrine organoids to reverse endocrine dysfunctions and progress in developing strategies for better engraftments. We also discuss the gap between preclinical and clinical research. Finally, we provide future perspectives for research on endocrine organoids for the development of more effective treatments for endocrine disorders.

Various Three-Dimensional Culture Methods and Cell Types for Exosome Production.

Cell-based therapies have been used as promising treatments for several untreatable diseases. However, cell-based therapies have side effects such as tumorigenesis and immune responses. To overcome these side effects, therapeutic effects of exosomes have been researched as replacements for cell-based therapies. In addition, exosomes reduced the risk that can be induced by cell-based therapies. Exosomes contain biomolecules such as proteins, lipids, and nucleic acids that play an essential role in cell-cell and cell-matrix interactions during biological processes. Since the introduction of exosomes, those have been proven perpetually as one of the most effective and therapeutic methods for incurable diseases. Much research has been conducted to enhance the properties of exosomes, including immune regulation, tissue repair, and regeneration. However, yield rate of exosomes is the critical obstacle that should be overcome for practical cell-free therapy. Three-dimensional (3D) culture methods are introduced as a breakthrough to get higher production yields of exosomes. For example, hanging drop and microwell were well known 3D culture methods and easy to use without invasiveness. However, these methods have limitation in mass production of exosomes. Therefore, a scaffold, spinner flask, and fiber bioreactor were introduced for mass production of exosomes isolated from various cell types. Furthermore, exosomes treatments derived from 3D cultured cells showed enhanced cell proliferation, angiogenesis, and immunosuppressive properties. This review provides therapeutic applications of exosomes using 3D culture methods.

Patellar tendon reconstruction using an Achilles tendon-bone block allograft for periprosthetic joint infection accompanied by patellar tendon disruption after total knee arthroplasty: a case report.

Background: As a complication of total knee arthroplasty (TKA), patella tendon disruption has been scarcely reported. Moreover, combined periprosthetic joint infection with patellar tendon disruption is even rare. This is a case report on successful treatment of a recurred periprosthetic joint infection accompanying the patellar tendon disruption after revision of TKA. Case Description: A 63-year-old woman presented with pain and exudate in the right knee. she had a history of two-stage revision TKA at another hospital for periprosthetic joint infection of right knee. With repeated incision and debridement, Achromobacter xylosoxidan was identified in samples collected from deep tissue. Therefore, two-stage revision TKA was performed. Intra-operatively, a complete defect of the patellar tendon was observed. Re-revision TKA was performed as a routine of two-stage revision of TKA for periprosthetic joint infection. Reconstruction of the patellar tendon defect was performed using an Achilles tendon-bone block allograft. Stability of allograft was confirmed at 30 degrees of flexion, and excellent implant placement was confirmed by postoperative radiographs. At the final follow-up 3 years after surgery, evidence of infectious sign was absent, and the range of flexion up to 120 degrees was recovered without extension lag. Normal locomotive gait was restored, and recreational activities previously performed were possible without discomfort. Conclusions: Proper reconstruction of extensor mechanism was achieved by patellar wrapping technique using an Achilles tendon-bone block allograft.

Ulmus davidiana 60% edible ethanolic extract for prevention of pericyte apoptosis in diabetic retinopathy.

Diabetic retinopathy (DR) is a disease that causes visual deficiency owing to vascular leakage or abnormal angiogenesis. Pericyte apoptosis is considered one of the main causes of vascular leakage in diabetic retina, but there are few known therapeutic agents that prevent it. Ulmus davidiana is a safe natural product that has been used in traditional medicine and is attracting attention as a potential treatment for various diseases, but its effect on pericyte loss or vascular leakage in DR is not known at all. In the present study, we investigated on the effects of 60% edible ethanolic extract of U. davidiana (U60E) and catechin 7-O-ß-D-apiofuranoside (C7A), a compound of U. davidiana, on pericyte survival and endothelial permeability. U60E and C7A prevented pericyte apoptosis by inhibiting the activation of p38 and JNK induced by increased glucose and tumor necrosis factor alpha (TNF-α) levels in diabetic retina. Moreover, U60E and C7A reduced endothelial permeability by preventing pericyte apoptosis in co-cultures of pericytes and endothelial cells. These results suggest that U60E and C7A could be a potential therapeutic agent for reducing vascular leakage by preventing pericyte apoptosis in DR.