Single-Cell Analyses Inform Mechanisms of Myeloid-Targeted Therapies in Colon Cancer.

Single-cell RNA sequencing (scRNA-seq) is a powerful tool for defining cellular diversity in tumors, but its application toward dissecting mechanisms underlying immune-modulating therapies is scarce. We performed scRNA-seq analyses on immune and stromal populations from colorectal cancer patients, identifying specific macrophage and conventional dendritic cell (cDC) subsets as key mediators of cellular cross-talk in the tumor microenvironment. Defining comparable myeloid populations in mouse tumors enabled characterization of their response to myeloid-targeted immunotherapy. Treatment with anti-CSF1R preferentially depleted macrophages with an inflammatory signature but spared macrophage populations that in mouse and human expresses pro-angiogenic/tumorigenic genes. Treatment with a CD40 agonist antibody preferentially activated a cDC population and increased Bhlhe40+ Th1-like cells and CD8+ memory T cells. Our comprehensive analysis of key myeloid subsets in human and mouse identifies critical cellular interactions regulating tumor immunity and defines mechanisms underlying myeloid-targeted immunotherapies currently undergoing clinical testing.

Iridium(III) carbene complexes as potent girdin inhibitors against metastatic cancers.

Many cancer-driving protein targets remain undruggable due to a lack of binding molecular scaffolds. In this regard, octahedral metal complexes with unique and versatile three-dimensional structures have rarely been explored as inhibitors of undruggable protein targets. Here, we describe antitumor iridium(III) pyridinium-N-heterocyclic carbene complex 1a, which profoundly reduces the viability of lung and breast cancer cells as well as cancer patient-derived organoids at low micromolar concentrations. Compound 1a effectively inhibits the growth of non-small-cell lung cancer and triple-negative breast cancer xenograft tumors, impedes the metastatic spread of breast cancer cells, and can be modified into an antibody-drug conjugate payload to achieve precise tumor delivery in mice. Identified by thermal proteome profiling, an important molecular target of 1a in cellulo is Girdin, a multifunctional adaptor protein that is overexpressed in cancer cells and unequivocally serves as a signaling hub for multiple pivotal oncogenic pathways. However, specific small-molecule inhibitors of Girdin have not yet been developed. Notably, 1a exhibits high binding affinity to Girdin with a Kd of 1.3 µM and targets the Girdin-linked EGFR/AKT/mTOR/STAT3 cancer-driving pathway, inhibiting cancer cell proliferation and metastatic activity. Our study reveals a potent Girdin-targeting anticancer compound and demonstrates that octahedral metal complexes constitute an untapped library of small-molecule inhibitors that can fit into the ligand-binding pockets of key oncoproteins.

Adaptive exchange sustains cullin-RING ubiquitin ligase networks and proper licensing of DNA replication.

Cop9 signalosome (CSN) regulates the function of cullin-RING E3 ubiquitin ligases (CRLs) by deconjugating the ubiquitin-like protein NEDD8 from the cullin subunit. To understand the physiological impact of CSN function on the CRL network and cell proliferation, we combined quantitative mass spectrometry and genome-wide CRISPR interference (CRISPRi) and CRISPR activation (CRISPRa) screens to identify factors that modulate cell viability upon inhibition of CSN by the small molecule CSN5i-3. CRL components and regulators strongly modulated the antiproliferative effects of CSN5i-3, and in addition we found two pathways involved in genome integrity, SCFFBXO5-APC/C-GMNN and CUL4DTL-SETD8, that contribute substantially to the toxicity of CSN inhibition. Our data highlight the importance of CSN-mediated NEDD8 deconjugation and adaptive exchange of CRL substrate receptors in sustaining CRL function and suggest approaches for leveraging CSN inhibition for the treatment of cancer.

Nonalternant Nanographenes Containing N-Centered Cyclopenta[ef]heptalene and Aza[7]Helicene Units.

Introducing helical subunits into negatively curved π-systems has a significant effect on both the molecular geometry and photophysical properties; however, the synthesis of these helical π-systems embedded with nonbenzenoid subunits remains challenging due to the high strain deriving from both the curvature and helix. Here, we report a family of nonalternant nanographenes containing a nitrogen (N)-doped cyclopenta[ef]heptalene unit. Among them, CPH-2 and CPH-3 can be viewed as hybrids of benzoannulated cyclopenta[ef]heptalene and aza[7]helicene. The crystal structures revealed a saddle geometry for CPH-1, a saddle-helix hybrid for CPH-2, and a twist-helix hybrid for CPH-3. Experimental measurements and theoretical calculations indicate that the saddle moieties in CPHs undergo flexible conformational changes at room temperature, while the aza[7]helicene subunit exhibits a dramatically increased racemization energy barrier (78.2 kcal mol-1 for CPH-2, 143.2 kcal mol-1 for CPH-3). The combination of the nitrogen lone electron pairs of the N-doped cyclopenta[ef]heptalene unit with the twisted helix fragments results in rich photophysics with distinctive fluorescence and phosphorescence in CPH-1 and CPH-2 and the similar energy fluorescence and phosphorescence in CPH-3. Both enantiopure CPH-2 and CPH-3 display distinct circular dichroism (CD) signals in the UV-vis range. Notably, compared to the reported fully π-extended helical nanographenes, CPH-3 exhibits excellent chiroptical properties with a |gabs| value of 1.0 × 10-2 and a |glum| value of 7.0 × 10-3; these values are among the highest for helical nanographenes.

Content of stress granules reveals a sex difference at the early phase of cold exposure in mice.

Adaptive thermogenesis is a vital physiological process for small endotherms. Female animals usually are more sensitive to cold temperature due to anatomical differences. Whether there is a sex difference at a molecular level is unclear. Stress granules (SGs) are dynamic organelles in which untranslated mRNAs reside during cellular stress. We hypothesize that the prompt response of SGs to cold stress can reveal the molecular difference between sexes. By analyzing the content in SGs of brown adipose tissue (BAT) at the early phase of cold stress for both sexes, we found more diverse mRNAs docked in the SGs in male mice and these mRNAs representing an extensive cellular reprogramming including apoptosis process and cold-induced thermogenesis. In female mice, the mRNAs in SGs dominantly were comprised of genes regulating ribonucleoprotein complex biogenesis. Conversely, the proteome in SGs was commonly characterized as structure molecules and RNA processing for both sexes. A spectrum of eukaryotic initiation factors (eIFs) was detected in the SGs of both female and male BAT, while those remained unchanged upon cold stress in male mice, various eIF3 and eIF4G isoforms were found reduced in female mice. Taken together, the unique features in SGs of male BAT reflected a prompt uncoupling protein-1 (UCP1) induction which was absent in female, and female, by contrast, were prepared for long-term transcriptional and translational adaptations.NEW & NOTEWORTHY The proteome analysis reveals that stress granules are the predominant form of cytosolic messenger ribonucleoproteins of brown adipose tissue (BAT) at the early phase of cold exposure in mice for both sexes. The transcriptome of stress granules of BAT unveils a sex difference of molecular response in early phase of cold exposure in mice, and such difference prepares for a prompt response to cold stress in male mice while for long-term adaptation in female mice.

A Noninferiority Trial Comparing 2 Days vs 5 Days of Terlipressin and Ceftriaxone in Terms of 5-Day Rebleeding for Patients With Acute Gastroesophageal Variceal Hemorrhage.

INTRODUCTION: This trial was to shorten the duration of both vasoconstrictors and prophylactic antibiotics to only 2 days in the therapy of acute gastroesophageal variceal hemorrhage. METHODS: After successful endoscopic hemostasis of gastroesophageal variceal hemorrhage, eligible patients were randomized to receive terlipressin infusion 1 mg per 6 hours and ceftriaxone 1 g daily for 5 days (group A) or a similar regimen for 2 days (group B). Primary end points were very early rebleeding at 5 days, and secondary end points included 48-hour hemostasis, 42-day rebleeding, and hospitalization days. RESULTS: Group A comprised 48 patients, and group B comprised 52 patients. Both groups were comparable in the severity of liver disease. Forty-eight-hour initial hemostasis was 95.8% in group A and 100% in group B ( P = 0.13). Very early rebleeding between 3 and 5 days occurred in 1 patient (2.1%) in group A and 2 patients (3.8%) in group B ( P = 0.60). The difference was 1.8% and the 95% confidence interval was -1.31% to 2.08%, which demonstrated noninferiority. Forty-two-day rebleeding occurred in 5 patients (10.4%) in group A and 4 patients (7.7%) in group B ( P = 0.63). The median hospitalization days were 8.5 ± 3.8 days in group A vs 5.6 ± 2.6 days in group B ( P < 0.001). DISCUSSION: After successful endoscopic hemostasis of acute variceal bleeding, combination of 2-day terlipressin infusion and ceftriaxone therapy was not inferior to the 5-day regimen in terms of very early rebleeding, with the advantage of shortening hospitalization stay.

Predictions of photophysical properties of phosphorescent platinum(II) complexes based on ensemble machine learning approach.

Cyclometalated Pt(II) complexes are popular phosphorescent emitters with color-tunable emissions. To render their practical applications as organic light-emitting diodes emitters, it is required to develop Pt(II) complexes with high radiative decay rate constant and photoluminescence (PL) quantum yield. Here, a general protocol is developed for accurate predictions of emission wavelength, radiative decay rate constant, and PL quantum yield based on the combination of first-principles quantum mechanical method, machine learning, and experimental calibration. A new dataset concerning phosphorescent Pt(II) emitters is constructed, with more than 200 samples collected from the literature. Features containing pertinent electronic properties of the complexes are chosen and ensemble learning models combined with stacking-based approaches exhibit the best performance, where the values of squared correlation coefficients are 0.96, 0.81, and 0.67 for the predictions of emission wavelength, PL quantum yield and radiative decay rate constant, respectively. The accuracy of the protocol is further confirmed using 24 recently reported Pt(II) complexes, which demonstrates its reliability for a broad palette of Pt(II) emitters.

Sterically Hindered Tetradentate [Pt(O

Described here are sterically hindered tetradentate [Pt(O^N^C^N)] emitters (Pt-1, Pt-2, and Pt-3) developed for stable and high-performance green phosphorescent organic light-emitting diodes (OLEDs). These Pt(II) emitters exhibit strong saturated green phosphorescence (λmax = 517-531 nm) in toluene and mCP thin films with emission quantum yields as high as 0.97, radiative rate constants (kr) as high as 4.4-5.3 × 105 s-1 and reduced excimer emission, and with a preferential horizontally oriented transition dipole ratio of up to 84%. Theoretical calculations show that p-(hetero)arene substituents at the periphery of the ligand scaffolds in Pt-1, Pt-2, and Pt-3 can i) enhance the spin-orbit coupling (SOC) between the lower singlet excited states and the T1 state, and S0→Sn (n = 1 or 2) transition dipole moment, and ii) introducing additional SOC activity and the bright 1ILCT[π(carbazole)→π*(N^C^N)] excited state (Pt-2 and Pt-3), which are the main contributors to the increased kr values. Utilizing these tetradentate Pt(II) emitters, green phosphorescent OLEDs are fabricated with narrow-band electroluminescence (FWHM down to 36 nm), high external quantum efficiency, current efficiency up to 27.6% and 98.7 cd A-1, and an unprecedented device lifetime (LT95) of up to 9270 h at 1000 cd m-2 under laboratory conditions.

Cytotoxicity effect and transcriptome analysis of PCV3-infected cells revealed potential viral pathogenic mechanisms.

Porcine circovirus type 3 (PCV3) has become an important pathogen in the global swine industry and poses a threat to pig health, but its pathogenic mechanism remains unknown. In this study, we constructed an innovative, linear infectious clone of PCV3 for rescuing the virus, and explored the transcriptome of infected cells to gain insights into its pathogenic mechanisms. Subsequently, an in vivo experiment was conducted to evaluate the pathogenicity of the rescued virus in pig. PCV3 nucleic acid was distributed across various organs, indicating systemic circulation via the bloodstream and viremia. Immunohistochemical staining also revealed a significant presence of PCV3 antigens in the spleen, lungs, and lymph nodes, indicating that PCV3 had tropism for these organs. Transcriptome analysis of infected ST cells revealed differential expression of genes associated with apoptosis, immune responses, and cellular metabolism. Notably, upregulation of genes related to the hypoxia-inducible factor-1 pathway, glycolysis, and the AGE/RAGE pathway suggests activation of inflammatory responses, ultimately leading to onset of disease. These findings have expanded our understanding of PCV3 pathogenesis, and the interplay between PCV3 and host factors.

One-Step Synthesis of Hollow CoS2 Spheres Derived from Polyoxometalate-Based Metal-Organic Frameworks with Peroxidase-like Activity.

In this work, hollow CoS2 particles were prepared by a one-step sulfurization strategy using polyoxometalate-based metal-organic frameworks as the precursor. The morphology and structure of CoS2 have been monitored by scanning electron microscopy, X-ray photoelectron spectroscopy, and X-ray powder diffraction. The mechanism for the formation of CoS2 is discussed. The reaction time and sulfur content are found to be important factors that affect the morphology and pure phase formation of CoS2, and a hollow semioctahedral morphology of CoS2 with open voids was obtained when the sulfur source was twice as large as the precursor and the reaction time was 24 h. The CoS2 (24 h) particles show an excellent peroxidase-like activity for the oxidation of colorless 3,3',5,5'-tetramethylbenzidine (TMB) to blue oxidized (oxTMB) by hydrogen peroxide. The polyoxometalate used as a precursor helps to stabilize oxTMB during catalytic oxidation, forming a stable curve platform for at least 8 min. Additionally, the colorimetric detection of hydroquinone is developed with a low detection limit of 0.42 µM. This research provides a new strategy to design hollow materials with high peroxidase-mimicking activity.

Benefits of Hepatitis C Viral Eradication: A Real-World Nationwide Cohort Study in Taiwan.

BACKGROUND: Chronic hepatitis C (CHC) increases the risk of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). This nationwide cohort study assessed the effectiveness of viral eradication of CHC. METHODS: The Taiwanese chronic hepatitis C cohort and Taiwan hepatitis C virus (HCV) registry are nationwide HCV registry cohorts incorporating data from 23 and 53 hospitals in Taiwan, respectively. This study included 27,577 individuals from these cohorts that were given a diagnosis of CHC and with data linked to the Taiwan National Health Insurance Research Database. Patients received either pegylated interferon and ribavirin or direct-acting antiviral agent therapy for > 4 weeks for new-onset LC and liver-related events. RESULTS: Among the 27,577 analyzed patients, 25,461 (92.3%) achieved sustained virologic response (SVR). The mean follow-up duration was 51.2 ± 48.4 months, totaling 118,567 person-years. In the multivariable Cox proportional hazard analysis, the hazard ratio (HR) for incident HCC was 1.39 (95% confidence interval [CI]: 1.00-1.95, p = 0.052) among noncirrhotic patients without SVR compared with those with SVR and 1.82 (95% CI 1.34-2.48) among cirrhotic patients without SVR. The HR for liver-related events, including HCC and decompensated LC, was 1.70 (95% CI 1.30-2.24) among cirrhotic patients without SVR. Patients with SVR had a lower 10-year cumulative incidence of new-onset HCC than those without SVR did (21.7 vs. 38.7% in patients with LC, p < 0.001; 6.0 vs. 18.4% in patients without LC, p < 0.001). CONCLUSION: HCV eradication reduced the incidence of HCC in patients with and without LC and reduced the incidence of liver-related events in patients with LC.

MicroRNA expression profiling in tears and blood as predictive biomarkers for anti-VEGF treatment response in wet age-related macular degeneration.

PURPOSE: This study aimed to investigate the potential of microRNAs (miRNAs) in tears, blood, and aqueous humor as biomarkers for predicting treatment response in wet age-related macular degeneration (AMD) patients undergoing anti-vascular endothelial growth factor (anti-VEGF) therapy. METHODS: In a single-center prospective cohort study, treatment-naïve wet AMD patients and age-matched controls were enrolled. Clinical data and miRNA levels (miR-199a-3p, miR-365-3p, miR-200b-3p, miR-195-5p, miR-335-5p, and miR-185-5p) in tears, blood, and aqueous humor were collected. Treatment response was categorized into responders and non-responders based on visual acuity and central subfield thickness. MiRNA levels were quantified using reverse-transcription PCR. Statistical analyses were performed, including ROC analysis, to evaluate predictive accuracy. RESULTS: Dysregulated miRNA profiles were observed in wet AMD tears and blood compared to controls. Specifically, miR-199a-3p, miR-195-5p, and miR-185-5p were upregulated, while miR-200b-3p was downregulated in tears. All six miRNAs were elevated in wet AMD blood samples. Notably, responders showed higher tear expression of miR-195-5p and miR-185-5p. Combining these miRNAs yielded the highest predictive power (AUC = 0.878, p = 0.006) for anti-VEGF responders. CONCLUSIONS: Dysregulated miRNA profiles in tears and blood suggest their potential as biomarkers for wet AMD. MiR-195-5p and miR-185-5p in tears demonstrate predictive value for anti-VEGF treatment responders. This study underscores the non-invasive prediction potential of miRNA tear analysis in wet AMD treatment responses.

Strong metal-metal Pauli repulsion leads to repulsive metallophilicity in closed-shell d8 and d10 organometallic complexes.

Metallophilicity is defined as the interaction among closed-shell metal centers, the origin of which remains controversial, particularly for the roles of spd orbital hybridization (mixing of the spd atomic orbitals of the metal atom in the molecular orbitals of metal complex) and the relativistic effect. Our studies reveal that at close M-M' distances in the X-ray crystal structures of d8 and d10 organometallic complexes, M-M' closed-shell interactions are repulsive in nature due to strong M-M' Pauli repulsion. The relativistic effect facilitates (n + 1)s-nd and (n + 1)p-nd orbital hybridization of the metal atom, where (n + 1)s-nd hybridization induces strong M-M' Pauli repulsion and repulsive M-M' orbital interaction, and (n + 1)p-nd hybridization suppresses M-M' Pauli repulsion. This model is validated by both DFT (density functional theory) and high-level coupled-cluster singles and doubles with perturbative triples computations and is used to account for the fact that the intermolecular or intramolecular Ag-Ag' distance is shorter than the Au-Au' distance, where a weaker Ag-Ag' Pauli repulsion plays an important role. The experimental studies verify the importance of ligands in intermolecular interactions. Although the M-M' interaction is repulsive in nature, the linear coordination geometry of the d10 metal complex suppresses the L-L' (ligand-ligand) Pauli repulsion while retaining the strength of the attractive L-L' dispersion, leading to a close unsupported M-M' distance that is shorter than the sum of the van der Waals radius (rvdw) of the metal atoms.

Platinum(II) N-heterocyclic carbene complexes arrest metastatic tumor growth.

Vimentin is a cytoskeletal intermediate filament protein that plays pivotal roles in tumor initiation, progression, and metastasis, and its overexpression in aggressive cancers predicted poor prognosis. Herein described is a highly effective antitumor and antimetastatic metal complex [PtII(C^N^N)(NHC2Bu)]PF6 (Pt1a; HC^N^N = 6-phenyl-2,2'-bipyridine; NHC= N-heterocyclic carbene) that engages vimentin via noncovalent binding interactions with a distinct orthogonal structural scaffold. Pt1a displays vimentin-binding affinity with a dissociation constant of 1.06 µM from surface plasmon resonance measurements and fits into a pocket between the coiled coils of the rod domain of vimentin with multiple hydrophobic interactions. It engages vimentin in cellulo, disrupts vimentin cytoskeleton, reduces vimentin expression in tumors, suppresses xenograft growth and metastasis in different mouse models, and is well tolerated, attributable to biotransformation to less toxic and renal-clearable platinum(II) species. Our studies uncovered the practical therapeutic potential of platinum(II)‒NHC complexes as effective targeted chemotherapy for combating metastatic and cisplatin-resistant cancers.

Subtotal Thigh Flap for Large Abdominal Wall Defect Reconstruction in Patient With Recurrent Dermatofibrosarcoma Protuberans: A Case Report and Literature Review.

BACKGROUND: Harvesting an adequate-sized flap is challenging for reconstructing large defects on the abdominal wall. A subtotal thigh flap would be one of the choices as it provides a well-vascularized large flap with muscle components. Moreover, dermatofibrosarcoma protuberans (DFSP) is a low-grade dermal neoplasm with a high recurrence rate. There is still no consensus on the extent of resection to prevent a recurrence. OBJECTIVES: We present a case of a patient who underwent the reconstruction of a large abdominal wall defect with a subtotal thigh flap after the resection of recurrent DFSP. MATERIALS AND METHODS: A 59-year-old man killed from a recurrent huge mass in the lower abdomen with an invasion of the small intestine. His baseline characteristics and records of operations, medications, and outcomes were reviewed. RESULT: After tumor excision, a 28 × 30-cm subtotal thigh flap was harvested from his left thigh to reconstruct the abdominal defect. A microvascular anastomosis with left deep inferior epigastric vessels was made eventually. The flap was in good condition, and the donor site was covered with a split-thickness skin graft. CONCLUSIONS: Subtotal thigh flap may be considered for large abdominal wall defect reconstruction as it allows good perfusion of relatively large skin paddles compared with other free flaps. Also, patients with DFSP need definite margin-free resection and close follow-up to prevent a recurrence.

Exacerbated gastrointestinal symptoms and long COVID in IBD patients with SARS-CoV-2 infection: A multi-center study from taiwan.

BACKGROUND/PURPOSE: Limited studies have addressed the exacerbation of symptoms and long COVID in inflammatory bowel disease (IBD) patients following non-severe COVID-19 infection, particularly with post-COVID-19 vaccination. We aim to investigate factors associated with exacerbated gastrointestinal symptoms (EGS) and long COVID in IBD patients with non-severe COVID-19, which is most common situation in daily practice. METHODS: This is an observational study by multiple centers in Taiwan from May 2020 to March 2023. We collected clinical manifestation, data, and medication information from IBD patients with non-severe COVID-19. EGS was defined as increased frequency of diarrhea, bloody stool, and abdomen pain within 14 days after SARS-COV-2 infection. Long COVID was defined following the guidelines of the World Health Organization. RESULTS: Out of 90 patients, most of them (88.9%) received at least standard two doses of COVID-19 vaccination and the majority (87.8%) were mild diseases of COVID-19.30% of patients experienced EGS during COVID-19 with higher ESR levels serving as a predictive factor (Odds ratio: 3.6, 95% confidence interval: 1.2-10.5, P = 0.02). 38.1% of those patients developed long COVID. The patients who experienced EGS during COVID-19 and with a history of longer IBD duration showed a significant association with long COVID (p = 0.03 and p = 0.02). CONCLUSIONS: Our study revealed that EGS and long COVID occurred in one third of IBD patients with non-severe COVID-19, even though most of them had received the standard plus booster vaccination. We identified associated factors for EGS and long COVID, emphasizing the importance of post-COVID-19 follow-up in IBD patients.

Blood transcriptomic signature in type-2 biomarker-low severe asthma and asthma control.

BACKGROUND: Patients with type-2 (T2) cytokine-low severe asthma often have persistent symptoms despite suppression of T2 inflammation with corticosteroids. OBJECTIVES: We sought to analyze whole blood transcriptome from 738 samples in T2-biomarker-high/-low patients with severe asthma to relate transcriptomic signatures to T2 biomarkers and asthma symptom scores. METHODS: Bulk RNA-seq data were generated for blood samples (baseline, week 24, week 48) from 301 participants recruited to a randomized clinical trial of corticosteroid optimization in severe asthma. Unsupervised clustering, differential gene expression analysis, and pathway analysis were performed. Patients were grouped by T2-biomarker status and symptoms. Associations between clinical characteristics and differentially expressed genes (DEGs) associated with biomarker and symptom levels were investigated. RESULTS: Unsupervised clustering identified 2 clusters; cluster 2 patients were blood eosinophil-low/symptom-high and more likely to be receiving oral corticosteroids (OCSs). Differential gene expression analysis of these clusters, with and without stratification for OCSs, identified 2960 and 4162 DEGs, respectively. Six hundred twenty-seven of 2960 genes remained after adjusting for OCSs by subtracting OCS signature genes. Pathway analysis identified dolichyl-diphosphooligosaccharide biosynthesis and assembly of RNA polymerase I complex as significantly enriched pathways. No stable DEGs were associated with high symptoms in T2-biomarker-low patients, but numerous associated with elevated T2 biomarkers, including 15 that were upregulated at all time points irrespective of symptom level. CONCLUSIONS: OCSs have a considerable effect on whole blood transcriptome. Differential gene expression analysis demonstrates a clear T2-biomarker transcriptomic signature, but no signature was found in association with T2-biomarker-low patients, including those with a high symptom burden.

Taiwan Society of Cardiology Heart Failure Registry 2020: Rationale and Design.

Background: Heart failure (HF) is a significant public health problem worldwide. Death and rehospitalization rates are similar across different HF phenotypes. However, the existing Taiwanese HF registries mainly enrolled inpatients with HF and reduced ejection fraction (HFrEF) before 2019, so their results may not apply to outpatients or patients with HF with mildly reduced ejection fraction (HFmrEF) and HF with preserved ejection fraction (HFpEF) phenotypes. Methods: The Taiwan Society of Cardiology Heart Failure Registry 2020 is a prospective, multicenter, observational registry that will enroll patients with HF from 27 hospitals in Taiwan between 2020 and 2022 and will be followed for two years. Patients eligible for enrollment include those admitted due to acute decompensated heart failure or outpatients with a history of hospitalization for heart failure within the past six months. The registry will collect patient demographics, medical history, HF diagnosis, medication use, examination results, and comorbidities. The registry plans to enroll 3,370 patients, with the distribution of HFrEF/HFmrEF/HFpEF as 59%/13%/28%. Follow-up intervals will occur every six months for up to two years to monitor clinical outcomes and major cardiac interventions. The registry will conclude in December 2024. Conclusions: The Taiwan Society of Cardiology Heart Failure Registry 2020 is a comprehensive and meticulous effort to demonstrate the epidemiology, adherence to guidelines, clinical outcomes, and disease progression of Taiwanese patients with HF in contemporary clinical practice.

Step-by-Step Electrocrystallization Processes to Make Multiblock Magnetic Molecular Heterostructures.

Assembling conductive or magnetic heterostructures by bulk inorganic materials is important for making functional electronic or spintronic devices, such as semiconductive p-doped and n-doped silicon for P-N junction diodes, alternating ferromagnetic and nonmagnetic conductive layers used in giant magnetoresistance (GMR). Nonetheless, there have been few demonstrations of conductive or magnetic heterostructures made by discrete molecules. It is of fundamental interest to prepare and investigate heterostructures based on molecular conductors or molecular magnets, such as single-molecule magnets (SMMs). Herein, we demonstrate the fabrication of a series of molecular heterostructures composed of (TTF)2M(pdms)2 (TTF = tetrathiafulvalene, M = Co(II), Zn(II), Ni(II), H2pdms = 1,2-bis(methanesulfonamido)benzene) multiple building blocks through a well-controlled step-by-step electrocrystallization growth process, where the Co(pdms)2, Ni(pdms)2, and Zn(pdms)2 anionic complex is a SMM, paramagnetic, and diamagnetic molecule, respectively. Magnetic and SMM properties of the heterostructures were characterized and compared to the parentage (TTF)2Co(pdms)2 complex. This study presents the first methodology for creating molecule-based magnetic heterostructural systems by electrocrystallization.

Metformin reduces hepatocellular carcinoma incidence after successful antiviral therapy in patients with diabetes and chronic hepatitis C in Taiwan.

BACKGROUND & AIMS: Diabetes mellitus (DM) is known to increase the risk of hepatocellular carcinoma (HCC) among individuals with chronic hepatitis C (CHC). We aimed to evaluate whether metformin reduces HCC risk among individuals with DM and CHC after successful antiviral therapy. METHODS: Individuals with CHC who achieved a sustained virological response (SVR) after interferon-based therapy were enrolled in a large-scale, multicenter cohort in Taiwan (T-COACH). Cases of HCC at least 1 year after SVR were identified through linkage to the catastrophic illness and cancer registry databases. RESULTS: Of 7,249 individuals with CHC enrolled in the study, 781 (10.8%) had diabetes and 647 (82.8%) were metformin users. During a median follow-up of 4.4 years, 227 patients developed new-onset HCC. The 5-year cumulative HCC incidence was 10.9% in non-metformin users and 2.6% in metformin users, compared to 3.0% in individuals without DM (adjusted hazard ratio [aHR] 2.83; 95% CI 1.57-5.08 and aHR 1.46; 95% CI 0.98-2.19, respectively). Cirrhosis was the most important factor significantly associated with higher HCC risk in Cox regression analysis, followed by DM non-metformin use, older age, male sex, and obesity; whereas hyperlipidemia with statin use was associated with a lower HCC risk. Using the two most crucial risk factors, cirrhosis and DM non-metformin use, we constructed a simple risk model that could predict HCC risk among individuals with CHC after SVR. Metformin use was shown to reduce the risk of all liver-related complications. CONCLUSIONS: Metformin use greatly reduced HCC risk after successful antiviral therapy in individuals with diabetes and CHC. A simple risk stratification model comprising cirrhosis and DM non-metformin use could predict long-term outcomes in individuals with CHC after SVR. IMPACT AND IMPLICATIONS: The current study provides evidence that metformin could reduce hepatocellular carcinoma (HCC) incidence after successful antiviral therapy among those with diabetes and chronic hepatitis C in a large-scale nationwide cohort study. Although successful antiviral therapy greatly reduces HCC risk in individuals with chronic hepatitis C, those with cirrhosis, diabetes, obesity, and the elderly remain at high risk of HCC development. We demonstrated that a simple risk model composed of two crucial unfavorable factors, cirrhosis and diabetes without metformin use, predicts the risk of HCC and major liver-related complications after successful antiviral therapy in individuals with chronic hepatitis C. Metformin use is highly recommended for individuals with diabetes and chronic hepatitis C after viral eradication to reduce the risk of HCC.