The association between tocilizumab and the secondary bloodstream infection maybe nonsignificant in hospitalized patients with SARS-CoV-2 infection: A cohort study.

BACKGROUND: Immunomodulatory agents, such as tocilizumab (TCZ), exert promising effects against SARS-CoV-2 infection. However, growing evidence indicates that using TCZ may carry higher risks of secondary bloodstream infection (sBSI). This study determined whether TCZ is associated with an increased risk of sBSI. METHODS: We retrospectively collected the demographic and clinical data of hospitalized patients with SARS-CoV-2 infection from two Taiwanese hospitals. The time-to-incident sBSI in the TCZ users and nonusers was compared using the log-rank test. A multivariate Cox proportional hazards model was performed to identify independent risk factors for sBSI. RESULTS: Between May 1 and August 31, 2021, among 453 patients enrolled, 12 (2.65 %) developed sBSI. These patients were in hospital for longer duration (44.2 ± 31.4 vs. 17.6 ± 14.3 days, p = 0.014). Despite sBSI being more prevalent among the TCZ users (7.1 % vs. 1.6 %, p = 0.005), Kaplan-Meier survival analysis and multivariate Cox proportional hazards model both revealed no significant difference in risks of sBSI between the TCZ users and nonusers [adjusted HR (aHR) = 1.32 (95 % confidence interval (CI) = 0.29-6.05), p = 0.724]. Female sex [aHR = 7.00 (95 % CI = 1.45-33.92), p = 0.016], heavy drinking [aHR = 5.39 (95 % CI = 1.01-28.89), p = 0.049], and mechanical ventilation [aHR = 5.65 (95 % CI = 1.67-19.30), p = 0.006] were independently associated with a higher sBSI risk. CONCLUSION: This real-world evidence indicates that in hospitalized patients with SARS-CoV-2 infection, TCZ does not significantly increase the risk of sBSI.

Fucoidan Enhances Cisplatin-induced Effects on SCC-25 Human Oral Cancer Cells by Inhibiting the PI3K/AKT Pathway.

BACKGROUND/AIM: Cisplatin is a drug for treating oral cancer. However, several previous studies indicate that oral cancer cells can develop resistance to cisplatin, which may result in a poor prognosis for patients with oral cancer. Fucoidan, a natural health product extracted from brown seaweed, has anticancer abilities against various types of cancer cell. This study evaluated whether fucoidan can enhance the sensitivity of oral cancer cells to cisplatin and explored the underlying mechanism. MATERIALS AND METHODS: SCC-25 cells were used in the present study and treated with 0.3125 mg/ml fucoidan, 12.5 µg/ml cisplatin, or 0.3125 mg/ml fucoidan plus 12.5 µg/ml cisplatin for 48 h, 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, enzyme-linked immunosorbent, and immunoblotting assays were performed to evaluate cell survival, cytokeratin-18 fragment release, and expression of markers of apoptosis and autophagy, respectively. RESULTS: Cotreatment with fucoidan enhanced cisplatin-induced reduction of SCC-25 cell survival compared to cisplatin alone. In addition, cotreatment also increased the expression of apoptosis markers, including activated caspase-8, activated caspase-9, activated caspase-3, and cleaved poly(ADP-ribose) polymerase (PARP), but did not increase the expression of the two autophagy markers studied, beclin and autophagy-related 12-autophagy-related 5 conjugate. Fucoidan significantly inhibited cisplatin-induced AKT serine/threonine kinase 1 activation, which promoted PARP cleavage, caspase-3 activation, and cytokeratin-18 fragment expression in SCC-25 cells. CONCLUSION: Fucoidan promoted cisplatin-induced effects by inhibiting phosphatidylinositol 4,5 bisphosphate 3 kinase/AKT serine/threonine kinase 1 activation induced by cisplatin. The results of this study may provide a basis for the possible application of the combination of fucoidan and cisplatin in the clinical treatment of oral cancer in the future to improve the prognosis of patients with oral cancer.

Attention, response inhibition, impulsivity, and decision-making within luteal phase in women with premenstrual dysphoric disorder.

Cognitive impairment is a key feature of depressive disorder. Various forms of cognitive function have yet to be investigated in women with premenstrual dysphoric disorder (PMDD) during early luteal (EL) and late luteal (LL) phases. Therefore, we evaluated response inhibition and attention in PMDD in these two phases. We also examined the associations between cognitive functions, impulsivity, decision-making style, and irritability. There is a total of 63 female participants with PMDD and 53 controls, as determined through psychiatric diagnostic interviewing and a weekly symptoms checklist. The participants completed a Go/No-go task, Dickman's impulsivity inventory, Preference for Intuition and Deliberation scale, and the Buss-Durkee Hostility Inventory: Chinese Version-Short Form at the EL and LL phases. The women with PMDD had poorer attention in the Go trials at the LL phase and poorer response inhibition in the No-go trials at the EL and LL phases. Repeated measures analysis of variance revealed an LL exacerbation of deficit in attention among PMDD group. In addition, impulsivity negatively correlated with response inhibition at the LL phase. Preference for deliberation correlated with attention at the LL phase. Women with PMDD experienced LL declined attention and impaired response inhibition across the luteal phase. Response inhibition is linked to impulsivity. The deficit in attention links preference for deliberation among women with PMDD. These results reveal the different courses in different domains of cognitive impairment in PMDD. Further studies are required to elucidate the mechanism underlying cognitive dysfunction in PMDD.

A lesion-selective albumin-CTLA4Ig as a safe and effective treatment for collagen-induced arthritis.

BACKGROUND: CTLA4Ig is a dimeric fusion protein of the extracellular domain of cytotoxic T-lymphocyte protein 4 (CTLA4) and an Fc (Ig) fragment of human IgG1 that is approved for treating rheumatoid arthritis. However, CTLA4Ig may induce adverse effects. Developing a lesion-selective variant of CTLA4Ig may improve safety while maintaining the efficacy of the treatment. METHODS: We linked albumin to the N-terminus of CTLA4Ig (termed Alb-CTLA4Ig) via a substrate sequence of matrix metalloproteinase (MMP). The binding activities and the biological activities of Alb-CTLA4Ig before and after MMP digestion were analyzed by a cell-based ELISA and an in vitro Jurkat T cell activation assay. The efficacy and safety of Alb-CTLA4Ig in treating joint inflammation were tested in mouse collagen-induced arthritis. RESULTS: Alb-CTLA4Ig is stable and inactive under physiological conditions but can be fully activated by MMPs. The binding activity of nondigested Alb-CTLA4Ig was at least 10,000-fold weaker than that of MMP-digested Alb-CTLA4Ig. Nondigested Alb-CTLA4Ig was unable to inhibit Jurkat T cell activation, whereas MMP-digested Alb-CTLA4Ig was as potent as conventional CTLA4Ig in inhibiting the T cells. Alb-CTLA4Ig was converted to CTLA4Ig in the inflamed joints to treat mouse collagen-induced arthritis, showing similar efficacy to that of conventional CTLA4Ig. In contrast to conventional CTLA4Ig, Alb-CTLA4Ig did not inhibit the antimicrobial responses in the spleens of the treated mice. CONCLUSIONS: Our study indicates that Alb-CTLA4Ig can be activated by MMPs to suppress tissue inflammation in situ. Thus, Alb-CTLA4Ig is a safe and effective treatment for collagen-induced arthritis in mice.

Precise atom manipulation through deep reinforcement learning.

Atomic-scale manipulation in scanning tunneling microscopy has enabled the creation of quantum states of matter based on artificial structures and extreme miniaturization of computational circuitry based on individual atoms. The ability to autonomously arrange atomic structures with precision will enable the scaling up of nanoscale fabrication and expand the range of artificial structures hosting exotic quantum states. However, the a priori unknown manipulation parameters, the possibility of spontaneous tip apex changes, and the difficulty of modeling tip-atom interactions make it challenging to select manipulation parameters that can achieve atomic precision throughout extended operations. Here we use deep reinforcement learning (DRL) to control the real-world atom manipulation process. Several state-of-the-art reinforcement learning (RL) techniques are used jointly to boost data efficiency. The DRL agent learns to manipulate Ag adatoms on Ag(111) surfaces with optimal precision and is integrated with path planning algorithms to complete an autonomous atomic assembly system. The results demonstrate that state-of-the-art DRL can offer effective solutions to real-world challenges in nanofabrication and powerful approaches to increasingly complex scientific experiments at the atomic scale.

Relationship between obesity-related parameters and chronic kidney disease in middle-aged and elderly populations in Taiwan: A community-based study.

Globally, obesity is a major health problem and can markedly increase the risk of various diseases, including type 2 diabetes mellitus, hypertension (HTN), dyslipidemia, and chronic kidney disease (CKD). The association of obesity-related parameters, such as lipid parameters and their ratio, with CKD in clinical settings is not well understood. This study aimed to investigate the association of obesity-related parameters with CKD in the middle-aged and elderly population in Taiwan. This cross-sectional, community-based study recruited 400 participants (141 males and 259 females) aged 50 years or over from a community health promotion project at the Linkou Chang Gung Memorial Hospital (Guishan District, Taoyuan City) in 2014. Each participant completed a questionnaire including personal information and medical history during a face-to-face interview. Laboratory data were obtained from blood and urine sampling. The data were analyzed using t-test, chi-square test, Pearson's correlation test, multivariate logistic regression, and receiver operating characteristic (ROC) analysis. A total of 81 participants were identified as having CKD [estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2 or urine albumin/creatinine ratio ≥30 mg/g], and their mean triglyceride/high-density lipoprotein cholesterol (TG/HDL-C) ratio was 3.37 ± 2.72. The mean TG/HDL-C ratio of the 319 participants without CKD was 2.35 ± 1.66. After adjusting for age, TG/HDL-C was significantly positively correlated with blood pressure, body mass index, waist circumference, and fasting plasma glucose but not low-density lipoprotein cholesterol. There was a negative correlation between TG/HDL-C and eGFR. Multiple logistic regression model analysis showed that TG/HDL-C was still significantly associated with CKD (OR: 1.17, 95% CI: 1.01-1.36, p = 0.04) after adjusting for multiple covariates. The cut-off point of TG/HDL-C as a predictor of CKD was 2.54 with an area under the ROC curve of 0.61 (95% CI: 0.53-0.68). There was a significant positive correlation between TG/HDL-C and several cardiovascular disease risk factors, including obesity indices. The TG/HDL-C ratio was significantly associated with the risk of CKD and demonstrated predictive ability for CKD in the middle-aged and elderly population. Further studies on its application in clinical settings are warranted.

Psychological distress among immigrant women who divorced: Resilience as a mediator.

PURPOSE: The purpose of this study was to investigate relationships among the demands of immigration, resilience, and psychological distress in divorced immigrant women, and determine the mediating effects of resilience on the relationship between demands of immigration and psychological distress. DESIGN: The cross-sectional study included 117 women who had immigrated and married Taiwanese men but later got divorced. METHODS: The Chinese health questionnaire-12 scale, the resilience scale-Chinese version, and the demands of immigration (DI) scale were used to measure in this study. A multiple regression and Sobel test were used to examine whether resilience mediated the relationship between demands of immigration and psychological distress. FINDINGS: In this study, 47% of the divorced immigrant women were experiencing psychological distress, and 25.6% exhibited high levels of demands of immigration. Women with psychological distress had higher demand scores (t = 2.592, p = 0.011) and lower resilience scores (t = -3.965, p < 0.001) compared to women without psychological distress. The demands of immigration negatively predicted resilience (t = -3.050, p = 0.003). Finally, resilience mediated the association of demands of immigration with psychological distress (z = 2.497, p = 0.0125). CONCLUSIONS: Relationships among the demands of immigration, resilience, and psychological distress in divorced immigrant women were demonstrated in this study. Resilience played an important role in the relationship between demands of immigration and psychological distress. CLINICAL RELEVANCE: Tailored programs that foster resilience to reduce risks of demands of immigration and psychological distress in this vulnerable population should be developed.

The clinical relevance of humoral immune responses to Globo H-KLH vaccine adagloxad simolenin (OBI-822)/OBI-821 and expression of Globo H in metastatic breast cancer.

An international randomized phase II trial of Globo H (GH) vaccine, adagloxad simolenin/OBI-821 in 349 patients with metastatic breast cancer showed longer progression-free survival (PFS) in vaccinated patients who developed anti-Globo H (anti-GH) IgG than those who did not and the placebo group. The impacts of anti-GH IgM and GH expression on peak anti-GH IgG and clinical outcome were further evaluated. The titers of anti-GH IgG and IgM were determined by ELISA. GH expression in tumor was examined by immunohistochemical staining. Immunophenotyping was conducted by flow cytometry. Adagloxad simolenin elicited anti-GH IgM which peaked at titers ≥1:80 between weeks 5 and 13. The mean anti-GH IgG titer peaked at week 41 and decreased thereafter on the completion of vaccination. One log increase in peak IgM was associated with 10.6% decrease in the HR of disease progression (HR: 0.894, 95% CI: 0.833 to 0.960, p=0.0019). Patients with anti-GH IgM ≥1:320 within first 4 weeks after vaccination had significantly higher maximum anti-GH IgM (p<0.0001) and IgG titers (p<0.0001) than those with <1:320. Moreover, the median PFS appears to be longer for patients with anti-GH IgM ≥1:320 within first 4 weeks than those with anti-GH IgM titer <1:320 (11.1 vs 7.3 months, p=0.164), but not statistically significant. Among patients with H score ≥80 for GH expression by immunohistochemistry, the vaccination group (n=42) seemed to have better PFS than the placebo group (n=23) (HR=0.59; 95% CI: 0.32 to 1.10, p=0.10), but the difference did not reach statistical significance. In addition, peak levels of anti-GH IgM were higher in patients who had lower percentage of activated regulatory T cells (Treg cells; CD4+CD45RA-Foxp3high) at baseline than those who had higher activated Treg cells (p=0.042). This study demonstrates that adagloxad simolenin induced both IgG and IgM antibodies against GH. Anti-GH IgM ≥1:320 within first 4 weeks or low activated Treg cells at baseline may help to select patients who are likely to produce a higher level of GH-specific IgM and IgG in the future.

The Effects of Horticultural Therapy on Sense of Coherence among Residents of Long-Term Care Facilities: A Quasi Experimental Design.

Promoting positive mental health is crucial for the elderly living in long-term care facilities (LTCFs). This study aims to examine the effectiveness of horticultural therapy on the level of sense of coherence (SOC) among older LTCF residents with relatively normal mental function. With convenient sampling, a total of 86 participants were recruited from 12 LTCFs in northeastern Taiwan. In the experimental group (n = 49), the mean (±standard deviation) score of SOC was 50.45 ± 6.07 at baseline and increased to 56.37 ± 7.20 (p < 0.001) after 12-week horticultural intervention. In contrast, the mean SOC score did not change significantly in the control group (n = 37) during the study period. Generalized estimating equation analysis showed that a significant interaction effect between group and time on the SOC score (p < 0.001). Our findings indicate that horticultural therapy is effective to strengthen the SOC level of older LTCF residents without dementia.

Inhibition of gut microbial ß-glucuronidase effectively prevents carcinogen-induced microbial dysbiosis and intestinal tumorigenesis.

The bidirectional interaction between carcinogens and gut microbiota that contributes to colorectal cancer is complicated. Reactivation of carcinogen metabolites by microbial ß-glucuronidase (ßG) in the gut potentially plays an important role in colorectal carcinogenesis. We assessed the chemoprotective effects and associated changes in gut microbiota induced by pre-administration of bacterial-specific ßG inhibitor TCH-3511 in carcinogen azoxymethane (AOM)-treated APCMin/+ mice. AOM induced intestinal ßG activity, which was reflected in increases in the incidence, formation, and number of tumors in the intestine. Notably, inhibition of gut microbial ßG by TCH-3511 significantly reduced AOM-induced intestinal ßG activity, decreased the number of polyps in both the small and large intestine to a frequency that was similar in mice without AOM exposure. AOM also led to lower diversity and altered composition in the gut microbiota with a significant increase in mucin-degrading Akkermansia genus. Conversely, mice treated with TCH-3511 and AOM exhibited a more similar gut microbiota structure as mice without AOM administration. Importantly, TCH-3511 treatment significant decreased Akkermansia genus and produced a concomitant increase in short-chain fatty acid butyrate-producing gut commensal microbes Lachnoospiraceae NK4A136 group genus in AOM-treated mice. Taken together, our results reveal a key role of gut microbial ßG in promoting AOM-induced gut microbial dysbiosis and intestinal tumorigenesis, indicating the chemoprotective benefit of gut microbial ßG inhibition against carcinogens via maintaining the gut microbiota balance and preventing cancer-associated gut microbial dysbiosis. Thus, the bacterial-specific ßG inhibitor TCH-3511 is a potential chemoprevention agent for colorectal cancer.

A universal in silico V(D)J recombination strategy for developing humanized monoclonal antibodies.

BACKGROUND: Humanization of mouse monoclonal antibodies (mAbs) is crucial for reducing their immunogenicity in humans. However, humanized mAbs often lose their binding affinities. Therefore, an in silico humanization method that can prevent the loss of the binding affinity of mAbs is needed. METHODS: We developed an in silico V(D)J recombination platform in which we used V(D)J human germline gene sequences to design five humanized candidates of anti-tumor necrosis factor (TNF)-α mAbs (C1-C5) by using different human germline templates. The candidates were subjected to molecular dynamics simulation. In addition, the structural similarities of their complementarity-determining regions (CDRs) to those of original mouse mAbs were estimated to derive the weighted interatomic root mean squared deviation (wRMSDi) value. Subsequently, the correlation of the derived wRMSDi value with the half maximal effective concentration (EC50) and the binding affinity (KD) of the humanized anti-TNF-α candidates was examined. To confirm whether our in silico estimation method can be used for other humanized mAbs, we tested our method using the anti-epidermal growth factor receptor (EGFR) a4.6.1, anti-glypican-3 (GPC3) YP9.1 and anti-α4ß1 integrin HP1/2L mAbs. RESULTS: The R2 value for the correlation between the wRMSDi and log(EC50) of the recombinant Remicade and those of the humanized anti-TNF-α candidates was 0.901, and the R2 value for the correlation between wRMSDi and log(KD) was 0.9921. The results indicated that our in silico V(D)J recombination platform could predict the binding affinity of humanized candidates and successfully identify the high-affinity humanized anti-TNF-α antibody (Ab) C1 with a binding affinity similar to that of the parental chimeric mAb (5.13 × 10-10). For the anti-EGFR a4.6.1, anti-GPC3 YP9.1, and anti-α4ß1 integrin HP1/2L mAbs, the wRMSDi and log(EC50) exhibited strong correlations (R2 = 0.9908, 0.9999, and 0.8907, respectively). CONCLUSIONS: Our in silico V(D)J recombination platform can facilitate the development of humanized mAbs with low immunogenicity and high binding affinities. This platform can directly transform numerous mAbs with therapeutic potential to humanized or even human therapeutic Abs for clinical use.

Metabolic Risk Factors Associated With Chronic Kidney Disease in a Middle-Aged and Elderly Taiwanese Population: A Cross-Sectional Study.

Background: This study aimed to quantify the proportion of participants with chronic kidney disease (CKD) and associated metabolic risk factors in a middle-aged and elderly population in Guishan District, Taoyuan City, Taiwan. Methods: This cross-sectional study enrolled residents aged 50-90 years living in one community. All participants received a standardized personal interview, including a structured questionnaire, anthropometric measurements, and blood samples collected for laboratory testing. CKD was defined as the presence of kidney damage (urine albumin-creatinine ratio ≥30 mg/g) or estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m2. Multiple logistic regression models were used to evaluate the risk factors associated with CKD. Results: A total of 400 participants were enrolled. The overall proportion of participants with CKD was 20.5% (95% confidence interval [CI]: 16.54-24.46%). The proportions of participants with CKD among those aged 50-64, 65-74, and 75 years and over were 17.7, 18.8, and 35.7%, respectively (p = 0.01). Multiple logistic regression model revealed that elevated blood pressure (odds ratio [OR] = 2.23, 95% CI: 1.16-4.30), hyperglycemia (OR = 2.87, 95% CI: 1.64-5.00), hyperuricemia (OR = 1.38, 95% CI: 1.14-1.69), and metabolic syndrome (OR = 2.30, 95% CI: 1.31-4.06) were significantly associated with CKD. Conclusions: The prevalence of CKD in the study population was high. Hypertension, hyperglycemia, hyperuricemia, and metabolic syndrome are significantly associated with CKD in a middle-aged and elderly population in Taiwan.

Gender Differences in the Association Between Obesity Indices and Chronic Kidney Disease Among Middle-Aged and Elderly Taiwanese Population: A Community-Based Cross-Sectional Study.

Background: Traditional risk factors for chronic kidney disease (CKD) include diabetes mellitus (DM), hypertension (HTN), and metabolic syndrome, which are health conditions related to obesity. We aimed to investigate which of the three obesity indices has the strongest association with CKD and to explore whether there are gender differences in these relationships in the middle-aged and elderly Taiwanese population. Methods: This was a cross-sectional, community-based study. It included 400 residents (141 males and 259 females, age 50-90 years) residing in a community in northern Taiwan. Each participant was asked to fill a questionnaire that collected personal information, medical history, medication use, and anthropometric measurements. The laboratory data were obtained by testing the blood and urine samples. The baseline characteristics were compared, and the obesity indices included body mass index (BMI), waist circumference (WC), and visceral adiposity index (VAI). CKD was defined as the presence of renal dysfunction (urine albumin-creatinine ratio ≥ 30 mg/g) or estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73m2. We used a multiple logistic regression model to evaluate the association between each obesity index and CKD for both genders. Further, we used the area under the receiver operating characteristic (ROC) curve (AUC) to examine the best obesity indices to predict CKD in different genders. Results: The average age of the subjects was 64.47 ± 8.45 years, and men were significantly older. CKD was found in 31 (22.0%) males and 50 (19.3%) females. In men, there was no significant difference between the CKD and non-CKD groups among the three obesity indices. However, in women, only VAI was significantly higher in subjects with CKD (1.9 [1.1, 3.4]) than in subjects without CKD (1.5 [1.0, 2.2]) (p-value = 0.03). The multivariate logistic regression revealed that even after adjusting for possible confounding factors, VAI was found to be an independent risk factor for CKD in women (OR: 1.32, 95% CI: 1.04-1.69, p = 0.02), but not in men (OR: 1.20, 95% CI: 0.85-1.69, p = 0.30). The AUC of VAI had a significant ability to predict CKD in women but not in men. Conclusion: Our results showed that among the three obesity indices, VAI had the strongest association with CKD compared to BMI and WC in women. In addition, VAI in women should be given more importance in the screening for CKD among the middle-aged and elderly Taiwanese population.

The Effects of a Social Participation App on Seniors.

BACKGROUND: Advancements in medical care have increased the average life span in many countries, resulting in a generally longer postretirement life span. However, retirees may find it difficult to adapt to retirement. Therefore, encouraging retirees to engage with society is important. PURPOSE: In this study, a senior social participation mobile software application (SSP-App) was developed to stimulate social participation among seniors with the goal of improving their social participation intentions and behaviors. METHODS: After developing the SSP-App based on user experiences, a quasi-experimental study was conducted. Participants were recruited from the Keelung Ren'ai Community Center. Next, Random Allocation Software Version 1.0.0 software was used to randomly allocate the participants into experimental and control groups. The 54 participants in the experimental group took part in an SSP-App program, whereas the 53 participants in the control group did not participate in any experimental treatment program. Measurements were conducted at Week 4 (T1) and Week 12 (T2) to evaluate the effects. Data were collected using a demographic datasheet, Geriatric Depression Scale-Short Form, Emotional and Social Support Scale, Social Participation Intention Scale, and Social Participation Behavior Scale. The generalized estimating equations method was used to determine intervention effectiveness. RESULTS: The SSP-App has six main functions, including an activity partner message board, an activity search function that provides information about different activities, a "Seniors Learning Kiosk" that provides useful information, transportation information, an activity planning and reminder system, and a "First-Aid Station." Most participants in the SSP-App precursor test expressed approval. At T1, effects were observed in social participation intention only. However, at T2, effects were observed in both social participation intention and social participation behavior. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: The SSP-App developed in this study uses information and communication technology and multiple strategies covering information provision, social support, education, and reminders. Social participation obstacles must be overcome to effectively provide seniors with social participation opportunities and improve their social participation.

Selective activation of pro-anti-IL-1ß antibody enhances specificity for autoinflammatory disorder therapy.

Canakinumab is a fully human monoclonal antibody that specifically neutralizes human interleukin (IL)-1ß and has been approved by the US Food and Drug Administration for treating different types of autoinflammatory disorders such as cryopyrin-associated periodic syndrome, tumor necrosis factor receptor-associated periodic syndrome and systemic juvenile idiopathic arthritis. However, long-term systemic neutralization of IL-1ß by Canakinumab may cause severe adverse events such as serious upper respiratory tract infections and inflammation, thereby decreasing the quality of life of patients. Here, we used an IgG1 hinge as an Ab lock to cover the IL-1ß-binding site of Canakinumab by linking with matrix metalloprotease 9 (MMP-9) substrate to generate pro-Canakinumab that can be specifically activated in the inflamed regions in autoinflammatory diseases to enhance the selectivity and safety of treatment. The Ab lock significantly inhibited the IL-1ß-binding by 68-fold compared with Canakinumab, and MMP-9 completely restored the IL-1ß neutralizing ability of pro-Canakinumab within 60 min and blocked IL-1ß-downstream signaling and IL-1ß-regulated genes (i.e., IL-6). It is expected that MMP-9 cleavable and efficient Ab lock will be able to significantly enhance the selective reaction of Canakinumab at the disease site and reduce the on-target toxicities of Canakinumab during systemic circulation, thereby showing potential for development to improve the safety and quality of life of patients with autoinflammatory disorders in the future.

Preclinical Studies of OBI-999: A Novel Globo H-Targeting Antibody-Drug Conjugate.

Globo H (GH), a hexasaccharide, is expressed at low levels in normal tissues but is highly expressed in multiple cancer types, rendering it a promising target for cancer immunotherapy. OBI-999, a novel antibody-drug conjugate, is derived from a conjugation of a GH-specific mAb with a monomethyl auristatin E (MMAE) payload through a site-specific ThioBridge and a cleavable linker. OBI-999 high homogeneity with a drug-to-antibody ratio of 4 (>95%) was achieved using ThioBridge. OBI-999 displayed GH-dependent cellular internalization and trafficked to endosome and lysosome within 1 and 5 hours, respectively. Furthermore, OBI-999 showed low nanomolar cytotoxicity in the assay with high GH expression on tumor cells and exhibited a bystander killing effect on tumor cells with minimal GH expression. Tissue distribution indicated that OBI-999 and free MMAE gradually accumulated in the tumor, reaching maximum level at 168 hours after treatment, whereas OBI-999 and free MMAE decreased quickly at 4 hours after treatment in normal organs. Maximum MMAE level in the tumor was 16-fold higher than in serum, suggesting that OBI-999 is stable during circulation and MMAE is selectively released in the tumor. Excellent tumor growth inhibition of OBI-999 was demonstrated in breast, gastric, and pancreatic cancer xenograft or lung patient-derived xenograft models in a dose-dependent manner. The highest nonseverely toxic dose in cynomolgus monkeys is 10 mg/kg determined by a 3-week repeated-dose toxicology study demonstrating an acceptable safety margin. Taken together, these results support further clinical development of OBI-999, which is currently in a phase I/II clinical study in multiple solid tumors (NCT04084366). OBI-999, the first GH-targeting ADC, displayed excellent tumor inhibition in animal models across multiple cancer types, including breast, gastric, pancreatic, and lung cancers, warranting further investigation in the treatment of solid tumors.

Arabidopsis JMJ17 promotes cotyledon greening during de-etiolation by repressing genes involved in tetrapyrrole biosynthesis in etiolated seedlings.

Arabidopsis histone H3 lysine 4 (H3K4) demethylases play crucial roles in several developmental processes, but their involvement in seedling establishment remain unexplored. Here, we show that Arabidopsis JUMONJI DOMAIN-CONTAINING PROTEIN17 (JMJ17), an H3K4me3 demethylase, is involved in cotyledon greening during seedling establishment. Dark-grown seedlings of jmj17 accumulated a high concentration of protochlorophyllide, an intermediate metabolite in the tetrapyrrole biosynthesis (TPB) pathway that generates chlorophyll (Chl) during photomorphogenesis. Upon light irradiation, jmj17 mutants displayed decreased cotyledon greening and reduced Chl level compared with the wild-type; overexpression of JMJ17 completely rescued the jmj17-5 phenotype. Transcriptomics analysis uncovered that several genes encoding key enzymes involved in TPB were upregulated in etiolated jmj17 seedlings. Consistently, chromatin immunoprecipitation-quantitative PCR revealed elevated H3K4me3 level at the promoters of target genes. Chromatin association of JMJ17 was diminished upon light exposure. Furthermore, JMJ17 interacted with PHYTOCHROME INTERACTING FACTOR1 in the yeast two-hybrid assay. JMJ17 binds directly to gene promoters to demethylate H3K4me3 to suppress PROTOCHLOROPHYLLIDE OXIDOREDUCTASE C expression and TPB in the dark. Light results in de-repression of gene expression to modulate seedling greening during de-etiolation. Our study reveals a new role for histone demethylase JMJ17 in controlling cotyledon greening in etiolated seedlings during the dark-to-light transition.

Development and Psychometric Evaluation of the Place Attachment for Community-Dwelling Older Adults Scale.

This study developed the Place Attachment for Community-Dwelling Older Adults (PACOA) scale and evaluated its psychometric properties. The PACOA was developed through a qualitative study and expert panels. A pilot study confirmed the 19-item PACOA which included five factors (meaning of life, dependency, feeling "in place," continuity, and social inclusion) were extracted. This model explained 60.803% of the variance. Cronbach's α of the PACOA and its subscales were .853 and .670 to .863, respectively, whereas the correlations between the PACOA and its subscales were .580 to .725 (p < .01). The criterion validity and test-retest reliability were .678 (p < .01) and r = .654 (p < .01). Our findings suggest that the PACOA is an indicator of the emotional connection between older adults and their places of residence. Future studies should address the older adult-place fit, the future connection characteristics, and the influence of place attachment on older adults' healthy lifestyle behaviors.

Fibrinogen-Like Protein 1 Serves as an Anti-Inflammatory Agent for Collagen-Induced Arthritis Therapy in Mice.

Fibrinogen-like protein 1 (FGL1) was recently identified as a major ligand of lymphocyte-activation gene-3 (LAG-3) on activated T cells and serves as an immune suppressive molecule for regulation of immune homeostasis. However, whether FGL1 has therapeutic potential for use in the T cell-induced the autoimmune disease, rheumatoid arthritis (RA), is still unknown. Here, we attempted to evaluate the effect of FGL1 protein on arthritis progression. We also evaluated potential adverse events in a collagen-induced arthritis (CIA) mouse model. We first confirmed that soluble Fgl1 protein could specifically bind to surface Lag-3 receptor on 3T3-Lag-3 cells and further inhibit interleukin (IL-2) and interferon gamma (IFNγ) secretion from activated primary mouse T cells by 95% and 43%, respectively. Intraperitoneal administration of Fgl1 protein significantly decreased the inflammatory cytokine level (i.e., IL-1ß and IL-6) in local paw tissue, and prevented joint inflammation, cellular infiltration, bone deformation and attenuated collagen-induced arthritis progression in vivo. We further demonstrated that exogenous Fgl1 does not cause obvious adverse events during treatment by monitoring body weight and liver weight, and assessing the morphology of several organs (i.e., heart, liver, spleen, lung and kidney) by pathological studies. We expect that Fgl1 protein may be suitable to serve as a potential therapeutic agent for treatment of RA or even other types of T cell-induced autoimmune or inflammatory diseases in the future.

Humanized bispecific antibody (mPEG × HER2) rapidly confers PEGylated nanoparticles tumor specificity for multimodality imaging in breast cancer.

BACKGROUND: Developing a universal strategy to improve the specificity and sensitivity of PEGylated nanoaparticles (PEG-NPs) for assisting in the diagnosis of tumors is important in multimodality imaging. Here, we developed the anti-methoxypolyethylene glycol (mPEG) bispecific antibody (BsAb; mPEG × HER2), which has dual specificity for mPEG and human epidermal growth factor receptor 2 (HER2), with a diverse array of PEG-NPs to confer nanoparticles with HER2 specificity and stronger intensity. RESULT: We used a one-step formulation to rapidly modify the nanoprobes with mPEG × HER2 and optimized the modified ratio of BsAbs on several PEG-NPs (Lipo-DiR, SPIO, Qdot and AuNP). The αHER2/PEG-NPs could specifically target MCF7/HER2 cells (HER2++) but not MCF7/neo1 cells (HER2+/-). The αHER2/Lipo-DiR and αHER2/SPIO could enhance the sensitivity of untargeted PEG-NPs on MCF7/HER2 (HER2++). In in vivo imaging, αHER2/Lipo-DiR and αHER2/SPIO increased the specific targeting and enhanced PEG-NPs accumulation at 175% and 187% on 24 h, respectively, in HER2-overexpressing tumors. CONCLUSION: mPEG × HER2, therefore, provided a simple one-step formulation to confer HER2-specific targeting and enhanced sensitivity and contrast intensity on HER2 positive tumors for multimodality imaging.