Structural modifications toward improved lead-203/lead-212 peptide-based image-guided alpha-particle radiopharmaceutical therapies for neuroendocrine tumors.

PURPOSE: The lead-203 (203Pb)/lead-212 (212Pb) elementally identical radionuclide pair has gained significant interest in the field of image-guided targeted alpha-particle therapy for cancer. Emerging evidence suggests that 212Pb-labeled peptide-based radiopharmaceuticals targeting somatostatin receptor subtype 2 (SSTR2) may provide improved effectiveness compared to beta-particle-based therapies for neuroendocrine tumors (NETs). This study aims to improve the performance of SSTR2-targeted radionuclide imaging and therapy through structural modifications to Tyr3-octreotide (TOC)-based radiopharmaceuticals. METHODS: New SSTR2-targeted peptides were designed and synthesized with the goal of optimizing the incorporation of Pb isotopes through the use of a modified cyclization technique; the introduction of a Pb-specific chelator (PSC); and the insertion of polyethylene glycol (PEG) linkers. The binding affinity of the peptides and the cellular uptake of 203Pb-labeled peptides were evaluated using pancreatic AR42J (SSTR2+) tumor cells and the biodistribution and imaging of the 203Pb-labeled peptides were assessed in an AR42J tumor xenograft mouse model. A lead peptide was identified (i.e., PSC-PEG2-TOC), which was then further evaluated for efficacy in 212Pb therapy studies. RESULTS: The lead radiopeptide drug conjugate (RPDC) - [203Pb]Pb-PSC-PEG2-TOC - significantly improved the tumor-targeting properties, including receptor binding and tumor accumulation and retention as compared to [203Pb]Pb-DOTA0-Tyr3-octreotide (DOTATOC). Additionally, the modified RPDC exhibited faster renal clearance than the DOTATOC counterpart. These advantageous characteristics of [212Pb]Pb-PSC-PEG2-TOC resulted in a dose-dependent therapeutic effect with minimal signs of toxicity in the AR42J xenograft model. Fractionated administrations of 3.7 MBq [212Pb]Pb-PSC-PEG2-TOC over three doses further improved anti-tumor effectiveness, resulting in 80% survival (70% complete response) over 120 days in the mouse model. CONCLUSION: Structural modifications to chelator and linker compositions improved tumor targeting and pharmacokinetics (PK) of 203/212Pb peptide-based radiopharmaceuticals for NET theranostics. These findings suggest that PSC-PEG2-TOC is a promising candidate for Pb-based targeted radionuclide therapy for NETs and other types of cancers that express SSTR2.

Pre-clinical evaluation of biomarkers for the early detection of nephrotoxicity following alpha-particle radioligand therapy.

PURPOSE: Cancer treatment with alpha-emitter-based radioligand therapies (α-RLTs) demonstrates promising tumor responses. Radiolabeled peptides are filtered through glomeruli, followed by potential reabsorption of a fraction by proximal tubules, which may cause acute kidney injury (AKI) and chronic kidney disease (CKD). Because tubular cells are considered the primary site of radiopeptides' renal reabsorption and potential injury, the current use of kidney biomarkers of glomerular functional loss limits the evaluation of possible nephrotoxicity and its early detection. This study aimed to investigate whether urinary secretion of tubular injury biomarkers could be used as an additional non-invasive sensitive diagnostic tool to identify unrecognizable tubular damage and risk of long-term α-RLT nephrotoxicity. METHODS: A bifunctional cyclic peptide, melanocortin 1 ligand (MC1L), labeled with [203Pb]Pb-MC1L, was used for [212Pb]Pb-MC1L biodistribution and absorbed dose measurements in CD-1 Elite mice. Mice were treated with [212Pb]Pb-MC1L in a dose-escalation study up to levels of radioactivity intended to induce kidney injury. The approach enabled prospective kidney functional and injury biomarker evaluation and late kidney histological analysis to validate these biomarkers. RESULTS: Biodistribution analysis identified [212Pb]Pb-MC1L reabsorption in kidneys with a dose deposition of 2.8, 8.9, and 20 Gy for 0.9, 3.0, and 6.7 MBq injected [212Pb]Pb-MC1L doses, respectively. As expected, mice receiving 6.7 MBq had significant weight loss and CKD evidence based on serum creatinine, cystatin C, and kidney histological alterations 28 weeks after treatment. A dose-dependent urinary neutrophil gelatinase-associated lipocalin (NGAL, tubular injury biomarker) urinary excretion the day after [212Pb]Pb-MC1L treatment highly correlated with the severity of late tubulointerstitial injury and histological findings. CONCLUSION: Urine NGAL secretion could be a potential early diagnostic tool to identify unrecognized tubular damage and predict long-term α-RLT-related nephrotoxicity.

Depressive symptoms, parenting attitude, and violent discipline among caregivers of left-behind children in rural China: a cross-sectional study.

BACKGROUND: The situation of mental health and discipline behaviors of left-behind children's caregivers were not optimistic in rural China. Caregivers' depression might increase the risk of using violent discipline. However, the specific ways in which depressive symptoms impact violent discipline have rarely been explored in rural areas. This study aims to assess the prevalence of violent discipline among left-behind children under 6 years of age in rural China and explore the potential mechanisms of how caregivers' depressive symptoms affect violent discipline. METHODS: We enrolled a total of 396 pairs of left-behind children and their caregivers in our study, which was conducted in 5 counties of Hebei, Henan, Jiangxi, Guizhou, and Sichuan provinces in China. The depressive symptoms of caregivers were measured by using Zung Self-rating Depression Scale (ZSDS) and violent discipline was assessed by the Child Discipline Module of Multiple Indicator Cluster Surveys (MICS). A self-designed questionnaire was utilized to measure caregiver's parenting attitude. Based on the cross-sectional data, controlling for potential confounders, structural equation modeling (SEM) was used to assess the direct and indirect effects of the mediation models by applying the weighted least squares with mean and variance adjusted (WLSMV) estimate. RESULTS: The prevalence of violent discipline, psychological aggression, and physical punishment was 72.7%, 59.3%, and 60.4% respectively of left-behind children under 6 years of age. According to the results of SEM, parenting attitude acted as a suppressor, suppressing the association between caregivers' depressive symptoms and physical punishment/psychological aggression/violent discipline. The caregivers' depressive symptoms positively influenced all the outcome variables by affecting parenting attitudes (p = 0.002, p = 0.013, p = 0.002). CONCLUSIONS: The presence of depressive symptoms in caregivers increases the use of violent discipline through negative parenting attitudes. The mental health status of primary caregivers of left-behind children in rural China needed emphasis and improvement.

A randomized trial of treatment for anterior cruciate ligament reconstruction by radial extracorporeal shock wave therapy.

OBJECTIVE: The aim of this study was to explore the effects of radial extracorporeal shock wave therapy (rESWT) in patients with anterior cruciate ligament(ACL) reconstruction(ACLR). METHODS: We conducted a randomized, controlled trial involving 72 eligible patients with ACL reconstruction in which we compared two strategies: the experimental group was standard rehabilitation plus rESWT and the control group was standard rehabilitation plus sham rESWT. The outcome was the change from baseline to 24 weeks in the average score on Lysholm knee joint score (LKS), range of motion (ROM), visual analogue scale (VAS) and International Knee Literature Committee (IKDC). RESULTS: Of 36 subjects assigned to rehabilitation plus rESWT, 4 lost to follow up. Of 36 assigned to rehabilitation plus sham rESWT, 5 lost to follow up. The LKS, ROM and IKDC scores of the experimental group were markedly increased at 3 and 6 weeks after treatment (P < 0.001), and the VAS was notably decreased (P < 0.001). However, there were no significant differences in the LKS, ROM, IKDC and VAS between the groups at 24 weeks after treatment (P > 0.05). CONCLUSION: The strategy of rehabilitation plus rESWT had better functional outcomes after ACL reconstruction. As such, our study demonstrates that rESWT is essential for patients with ACL reconstruction. Early use of rESWT can improve joint function, pain relief and ability of daily living. rESWT has a positive effect on the overall rehabilitation of patients.

Family responsive care mediating the home visiting effects on left-behind children's early development in rural China.

BACKGROUND: The early development of left-behind children requires great concern and improvement. Yet, current interventions for left-behind children are mainly focussed on children older than 3. This study aims to assess the effectiveness of a home visiting programme on family responsive care and early development of rural left-behind children and examine whether family responsive care mediates the effects of intervention on child development. METHODS: A quasi-experimental study design was utilized in this study. A stratified clustered sampling was employed to choose villages in programme towns into intervention group. A control village was matched with every intervention village. All of the left-behind children and their caregivers meeting the inclusion criteria in the chosen villages were enrolled in the survey. The outcomes included child development, caregiver's early stimulation, parent-child communication, and learning materials. Baseline assessments were conducted in 2018, and endline assessments were conducted in 2020. RESULTS: In the endline survey, we enrolled 608 children with 258 in the intervention group and 350 in the control group. Left-behind children in the intervention group were less likely to have development delay compared with the control group (odds ratio [OR] = 0.59, 95% confidence interval [CI]: 0.36, 0.96). Migrant parents of children in the intervention group showed higher proportion of expressing emotional support to their children when communicating (OR = 1.69, 95% CI: 1.05, 2.72). Children who received home visits more than once per 2 months had lower level of suspected development delay than children in the control group (OR = 0.34, 95% CI: 0.18, 0.68). Caregiver's early stimulation and migrant parents' emotional support to left-behind children mediated the intervention dose and left-behind children's development. CONCLUSION: Caregiver's early stimulation mediates the intervention and child's development. The findings suggest a promising future for scaling similar early childhood development interventions for left-behind children in rural settings.

The application of extracorporeal shock wave therapy in the treatment of temporomandibular joint disorders in a preliminary, small sample study.

OBJECTIVE: The aim of this study was to investigate the efficacy of low-intensity, high-frequency shock waves in the treatment of temporomandibular joint disorders. METHODS: Twenty-six patients with temporomandibular joint disorder admitted to the Second Hospital of Shanxi Medical University from August 2022 to December 2022 were selected as study subjects and randomly divided into two groups, A and B, with 13 patients each. In Group A, there were 5 males and 8 females with an average age of 38.85 ± 11.03 years. In Group B, there were 4 males and 9 females with an average age of 39.15 ± 11.16 years. Group A was the control group, which received routine treatment (manual massage + transcutaneous electrical nerve stimulation + ultrashort wave therapy) plus sham shock wave therapy; Group B was the experimental group, which received routine treatment (manual massage + transcutaneous electrical nerve stimulation + ultrashort wave therapy) plus shock wave therapy. The routine treatment was administered once/day, five times per week for a total of 2 weeks of treatment. In addition, shock wave therapy was administered once every 5 days, and the treatment was administered three times. The treatment period was 2 weeks, and the two groups were compared before treatment, at the end of the treatment period, and 4 weeks after treatment. The pain level of the two groups was assessed by the visual analogue scale (VAS) before and after treatment, and the temporomandibular opening index (TOI) before and after treatment was compared between the two groups. VAS and TOI scores were evaluated using the Mann-Whitney U-test, the Kruskal-Wallis H-test and two-way ANOVA. RESULTS: There was no significant difference in the VAS score and temporomandibular opening index between the two groups before treatment (p = .829 and .75, respectively). After 2 weeks of treatment, the VAS score and temporomandibular joint opening index of both groups were significantly improved compared to those before therapy. In addition, the VAS score and temporomandibular joint opening index in the experimental group were significantly better than those in the control group (p < .001 and <.001, respectively). There was a small increase in scores 4 weeks after the treatment compared to just after the treatment period, but the difference was not significant. CONCLUSION: This is a preliminary small sample study that demonstrates the positive effect of using low-intensity, high-frequency shock waves on the treatment of temporomandibular joint disorders and is worthy of clinical promotion.

Parental Migration Trajectories From Childhood Through Adolescence: Longitudinal Impact on Emotional and Behavioral Problems Among Chinese Adolescents.

It is estimated that there are about 23% of all children in China experiencing parental migration and being left behind at hometown. Existing research indicated a significant association between parental migration and children development but overlooked the dynamic changes in family structure caused by parental migration. In this study, data was derived from a nationally representative longitudinal survey-the China Family Panel Studies. The main analyses employed four waves of data (2012, 2014, 2016, and 2018) and included 1401 adolescents aged 10-15 years (Mean:12.35, SD:1.67; 54.2% female). Six typical trajectories of parental migration capturing both migration status at each timepoint and changes in the status across six years were created. Children's depression and internalizing problems and externalizing problems were concerned outcomes. The mediating roles of the caregiver-child interaction and caregiver's depression were examined. Adolescents in the trajectory group described as experiencing transitions between being left behind by both parents and non had a higher risk of depression and internalizing and externalizing problems. Caregivers' depression was a significant mediator between parental migration and adolescent depression.

Oxymatrine suppresses colorectal cancer progression by inhibiting NLRP3 inflammasome activation through mitophagy induction in vitro and in vivo.

Chinese herb Radix sophorae tonkinensis extract oxymatrine shows anticancer effects. This study evaluated the role of oxymatrine in colorectal cancer (CRC) and the underlying molecular events in vitro and in vivo. CRC cells were treated with different doses of oxymatrine to assess cell viability, reactive oxygen species production, gene expression, and gene alterations. Meanwhile, mouse xenograft and liver metastasis models were used to assess the effects of oxymatrine using histology examination, transmission electron microscopy, and Western blot, respectively. Our results showed that oxymatrine treatment triggered CRC cell mitophagy to inhibit CRC cell growth, migration, invasion, and metastasis in vitro and in vivo. At the gene level, oxymatrine inhibited LRPPRC to promote Parkin translocation into the mitochondria and reduce the mitophagy-activated NLRP3 inflammasome. Thus, oxymatrine had an anticancer activity through LRPPRC inhibition, mitophagy induction, and NLRP3 inflammasome suppression in the CRC cell xenograft and liver metastasis models. In conclusion, the study demonstrates the oxymatrine anti- CRC activity through its unique role in regulating CRC cell mitophagy and NLRP3 inflammasome levels in vitro and in vivo.

Mobile Payment Protocol with Deniably Authenticated Property.

Mobile payment services have been widely applied in our daily life, where users can conduct transactions in a convenient way. However, critical privacy concerns have arisen. Specifically, a risk of participating in a transaction is the disclosure of personal privacy. This might occur if, for example, the user pays for some special medicine, such as AIDS medicine or contraceptives. In this paper, we propose a mobile payment protocol that is suitable for mobile devices only with limited computing resources. In particular, the user in a transaction can confirm the identity of others in the same transaction while the user cannot show convincing evidence to prove that others also take part in the same transactions. We implement the proposed protocol and test its computation overhead. The experiment results corroborate that the proposed protocol is suitable for mobile devices with limited computing resources.

Synthesis and evaluation of Diaza-Crown Ether-Backboned chelator containing hydroxamate groups for Zr-89 chelation chemistry.

Zirconium-89 (89Zr) has been explored for molecularly targeted positron emission tomography (PET) imaging of various diseases. We synthesized and evaluated a novel chelator (DA-18C6-BHA) for 89Zr. The new chelator is structured on a macrocyclic backbone (1,10-diaza-18-crown-6) and contains hydroxamates as acyclic donor groups. The new chelator ((DA-18C6-BHA) was rapidly labeled with 89Zr under mild conditions. The 89Zr-labeled DA-18C6-BHA complex remained stable in human serum and apotransferrin for 7 days. When challenged with excess EDTA solution, 89Zr-labeled DA-18C6-BHA was shown to hold 89Zr without losing considerable radioactivity to EDTA. The 89Zr-labeled DA-18C6-BHA complex displayed high complex stability in normal mice as evidenced by low bone uptake.

Dosimetry of [212Pb]VMT01, a MC1R-Targeted Alpha Therapeutic Compound, and Effect of Free 208Tl on Tissue Absorbed Doses.

[212Pb]VMT01 is a melanocortin 1 receptor (MC1R) targeted theranostic ligand in clinical development for alpha particle therapy for melanoma. 212Pb has an elementally matched gamma-emitting isotope 203Pb; thus, [203Pb]VMT01 can be used as an imaging surrogate for [212Pb]VMT01. [212Pb]VMT01 human serum stability studies have demonstrated retention of the 212Bi daughter within the chelator following beta emission of parent 212Pb. However, the subsequent alpha emission from the decay of 212Bi into 208Tl results in the generation of free 208Tl. Due to the 10.64-hour half-life of 212Pb, accumulation of free 208Tl in the injectate will occur. The goal of this work is to estimate the human dosimetry for [212Pb]VMT01 and the impact of free 208Tl in the injectate on human tissue absorbed doses. Human [212Pb]VMT01 tissue absorbed doses were estimated from murine [203Pb]VMT01 biodistribution data, and human biodistribution values for 201Tl chloride (a cardiac imaging agent) from published data were used to estimate the dosimetry of free 208Tl. Results indicate that the dose-limiting tissues for [212Pb]VMT01 are the red marrow and the kidneys, with estimated absorbed doses of 1.06 and 8.27 mGyRBE = 5/MBq. The estimated percent increase in absorbed doses from free 208Tl in the injectate is 0.03% and 0.09% to the red marrow and the kidneys, respectively. Absorbed doses from free 208Tl result in a percent increase of no more than 1.2% over [212Pb]VMT01 in any organ or tissue. This latter finding indicates that free 208Tl in the [212Pb]VMT01 injectate will not substantially impact estimated tissue absorbed doses in humans.

Impact of parent-child separation on children's social-emotional development: a cross-sectional study of left-behind children in poor rural areas of China.

BACKGROUND: Parent-child separation is a considerable adversity for left-behind children (LBC), but there is little evidence on the association between detailed characteristics of parent-child separation and social-emotional development among LBC. This study examined the characteristics of parent-child separation and its impacts on developmental delay among under-3 LBC in poor rural China. METHODS: We used data from 811 LBC surveyed in five poor counties in rural China in 2018. Detailed characteristics of their parental migration were recalled by their primary caregivers in face-to-face interviews. The children's social-emotional development was measured by using the Ages and Stages Questionnaire: Social-Emotional. Logistic regression was employed to examine the association of detailed characteristics of parent-child separation with early social-emotional problems after adjusting for the children's and primary caregivers' sociodemographic characteristics. RESULTS: 287 (35.4%) children were left behind by fathers and cared for by mothers (FM-MC), while 524 (64.6%) were left behind by both parents and cared for by grandparents (PM-GC). The rate of social-emotional problems among LBC was 36.8% (PM-GC vs FM-MC: 40.6% vs 29.5%; aOR 1.51, 95% CI: 1.06 to 2.16). For paternal migration, the medians of the child's age at the first migration and average duration per migration were 3 months (IQR: 1 to 9 months) and 4.48 months (IQR: 2.38 to 7.54 months), respectively. For maternal migration, the corresponding values were 9 months (IQR: 6 to 13 months) and 4.65 months (IQR: 2.71 to 7.62 months), respectively. On average, LBC had been separated from fathers for 72% of their life due to paternal migration and from mothers for 52% of their life due to maternal migration. No significant association was found between the detailed characteristics of paternal migration and social-emotional development among LBC, while social-emotional problems among LBC were significantly associated with the proportion of cumulative duration of maternal migration in the child's lifetime (aOR 2.83; 95% CI: 1.13 to 7.10). CONCLUSIONS: LBC under 3 years had a high risk of social-emotional problems in poor rural China. Cumulative exposure to maternal migration may be detrimental to LBC's early social-emotional development. Programs are necessary to support these children as well as their families.

Enhancing the Efficacy of Melanocortin 1 Receptor-Targeted Radiotherapy by Pharmacologically Upregulating the Receptor in Metastatic Melanoma.

Melanocortin 1 receptor (MC1R) is under investigation as a target for drug delivery for metastatic melanoma therapy and imaging. The purpose of this study was to determine the potential of using BRAF inhibitors (BRAFi) and histone deacetylase inhibitors (HDACi) to enhance the delivery of MC1R-targeted radiolabeled peptide ([212Pb]DOTA-MC1L) by pharmacologically upregulating the MC1R expression in metastatic melanoma cells and tumors. MC1R expression was analyzed in de-identified melanoma biopsies by immunohistochemical staining. Upregulation of MC1R expression was determined in BRAFV600E cells (A2058) and BRAF wild-type melanoma cells (MEWO) by quantitative real-time polymerase chain reaction, flow cytometry, and receptor-ligand binding assays. The role of microphthalmia-associated transcription factor (MITF) in the upregulation of MC1R was also examined in A2058 and MEWO cells. The effectiveness of [212Pb]DOTA-MC1L α-particle radiotherapy in combination with BRAFi and/or HDACi was determined in athymic nu/nu mice bearing A2058 and MEWO human melanoma xenografts. High expression of MC1R was observed in situ in clinical melanoma biopsies. BRAFi and HDACi significantly increased the MC1R expression (up to 10-fold in mRNA and 4-fold in protein levels) via MITF-dependent pathways, and this increase led to enhanced ligand binding on the cell surface. Inhibition of MITF expression antagonized the upregulation of MC1R in both BRAFV600E and BRAFWT cells. Combining [212Pb]DOTA-MC1L with BRAFi and/or HDACi improved the tumor response by increasing the delivery of 212Pb α-particle emissions to melanoma tumors via augmented MC1R expression. These data suggest that FDA-approved HDACi and BRAFi could improve the effectiveness of MC1R-targeted therapies by enhancing drug delivery via upregulated MC1R.

Calcitriol regulates angiotensin-converting enzyme and angiotensin converting-enzyme 2 in diabetic kidney disease.

To investigate the effects of calcitriol on angiotensin-converting enzyme (ACE) and ACE2 in diabetic nephropathy. Streptozotocin (STZ) induced diabetic rats were treated with calcitriol for 16 weeks. ACE/ACE2 and mitogen activated protein kinase (MAPK) enzymes were measured in the kidneys of diabetic rats and rat renal tubular epithelial cells exposed to high glucose. Calcitriol reduced proteinuria in diabetic rats without affecting calcium-phosphorus metabolism. ACE and ACE2 levels were significantly elevated in diabetic rats compared to those in control rats. The increase in ACE levels was greater than that of ACE2, leading to an elevated ACE/ACE2 ratio. Calcitriol reduced ACE levels and ACE/ACE2 ratio and increased ACE2 levels in diabetic rats. Similarly, high glucose up-regulated ACE expression in NRK-52E cells, which was blocked by the p38 MAPK inhibitor SB203580, but not the extracellular signal-regulated kinase (ERK) inhibitor FR180204 or the c-Jun N-terminal kinase (JNK) inhibitor SP600125. High glucose down-regulated ACE2 expression, which was blocked by FR180204, but not SB203580 or SP600125. Incubation of cells with calcitriol significantly inhibited p38 MAPK and ERK phosphorylation, but not JNK phosphorylation, and effectively attenuated ACE up-regulation and ACE2 down-regulation in high glucose conditions. The renoprotective effects of calcitriol in diabetic nephropathy were related to the regulation of tubular levels of ACE and ACE2, possibly by p38 MAPK or ERK, but not JNK pathways.

Hierarchical deep reinforcement learning for self-adaptive economic dispatch.

It is challenging to accurately model the overall uncertainty of the power system when it is connected to large-scale intermittent generation sources such as wind and photovoltaic generation due to the inherent volatility, uncertainty, and indivisibility of renewable energy. Deep reinforcement learning (DRL) algorithms are introduced as a solution to avoid modeling the complex uncertainties and to adapt the fluctuation of uncertainty by interacting with the environment and using feedback to continuously improve their strategies. However, the large-scale nature and uncertainty of the system lead to the sparse reward problem and high-dimensional space issue in DRL. A hierarchical deep reinforcement learning (HDRL) scheme is designed to decompose the process of solving this problem into two stages, using the reinforcement learning (RL) agent in the global stage and the heuristic algorithm in the local stage to find optimal dispatching decisions for power systems under uncertainty. Simulation studies have shown that the proposed HDRL scheme is efficient in solving power system economic dispatch problems under both deterministic and uncertain scenarios thanks to its adaptation system uncertainty, and coping with the volatility of uncertain factors while significantly improving the speed of online decision-making.

Study of whey protein on muscle mass and functional rehabilitation in postoperative total knee arthroplasty patients.

BACKGROUND: Patients who underwent total knee arthroplasty (TKA) often experience muscle loss due to pain and limited mobility. Nutritional supplementation and rehabilitation may positively affect the decline in muscle function. OBJECTIVE: The purpose of this study is to evaluate whether whey protein intervention, in addition to conventional rehabilitation training, is beneficial in improving muscle function and quality of life in patients after TKA. METHODS: 72 patients who met the criteria were selected for this randomized controlled study. For the experimental group, whey protein was used as a daily supplement for 12 weeks, while the control group was given a placebo, during which both groups received conventional rehabilitation training. Muscle strength and each of the secondary observables needed to be measured and statistically analyzed preoperatively and at 4, 8, and 12 weeks post-intervention. RESULTS: In total, 62 subjects completed the study: 32 in the experimental group and 30 in the control group. Both groups showed significant improvement in muscle strength, VAS, ROM, AKS and leg circumference after 12 weeks of treatment. Compared to the control group, patients in the experimental group showed significant improvement in muscle strength, VAS, ROM, AKS and leg circumference (p= 0.001, p= 0.002, p= 0.001, p= 0.001, p= 0.001, respectively) after 12 weeks of treatment. CONCLUSION: The 12-week intervention of whey protein nutritional supplement showed significant improvement in muscle mass and function among post-TKA patients besides aiding with conventional rehabilitation exercise.

212Pb-Pretargeted Theranostics for Pancreatic Cancer.

Although pancreatic ductal adenocarcinoma (PDAC) is associated with limited treatment options and poor patient outcomes, targeted α-particle therapy (TAT) represents a promising development in the field. TAT shows potential in treating metastatic cancers, including those that have become resistant to conventional treatments. Among the most auspicious radionuclides stands the in vivo α-generator 212Pb. Combined with the imaging-compatible radionuclide 203Pb, this theranostic match is a promising modality rapidly translating into the clinic. Methods: Using the pretargeting approach between a radiolabeled 1,2,4,5-tetrazine (Tz) tracer and a trans-cyclooctene (TCO) modified antibody, imaging and therapy with radiolead were performed on a PDAC tumor xenograft mouse model. For therapy, 3 cohorts received a single administration of 1.1, 2.2, or 3.7 MBq of the pretargeting agent, [212Pb]Pb-DO3A-PEG7-Tz, whereby administered activity levels were guided by dosimetric analysis. Results: The treated mice were holistically evaluated; minimal-to-mild renal tubular necrosis was observed. At the same time, median survival doubled for the highest-dose cohort (10.7 wk) compared with the control cohort (5.1 wk). Conclusion: This foundational study demonstrated the feasibility and safety of pretargeted TAT with 212Pb in PDAC while considering dose limitations and potential adverse effects.

Loss of monopolar spindle-binding protein 3B expression promotes colorectal cancer invasiveness by activation of target of rapamycin kinase/autophagy signaling.

BACKGROUND: Monopolar spindle-binding protein 3B (MOB3B) functions as a signal transducer and altered MOB3B expression is associated with the development of human cancers. AIM: To investigate the role of MOB3B in colorectal cancer (CRC). METHODS: This study collected 102 CRC tissue samples for immunohistochemical detection of MOB3B expression for association with CRC prognosis. After overexpression and knockdown of MOB3B expression were induced in CRC cell lines, changes in cell viability, migration, invasion, and gene expression were assayed. Tumor cell autophagy was detected using transmission electron microscopy, while nude mouse xenograft experiments were performed to confirm the in-vitro results. RESULTS: MOB3B expression was reduced in CRC vs normal tissues and loss of MOB3B expression was associated with poor CRC prognosis. Overexpression of MOB3B protein in vitro attenuated the cell viability as well as the migration and invasion capacities of CRC cells, whereas knockdown of MOB3B expression had the opposite effects in CRC cells. At the molecular level, microtubule-associated protein light chain 3 II/I expression was elevated, whereas the expression of matrix metalloproteinase (MMP)2, MMP9, sequestosome 1, and phosphorylated mechanistic target of rapamycin kinase (mTOR) was downregulated in MOB3B-overexpressing RKO cells. In contrast, the opposite results were observed in tumor cells with MOB3B knockdown. The nude mouse data confirmed these in-vitro findings, i.e., MOB3B expression suppressed CRC cell xenograft growth, whereas knockdown of MOB3B expression promoted the growth of CRC cell xenografts. CONCLUSION: Loss of MOB3B expression promotes CRC development and malignant behaviors, suggesting a potential tumor suppressive role of MOB3B in CRC by inhibition of mTOR/autophagy signaling.

The Potential Use of Fungal Co-Culture Strategy for Discovery of New Secondary Metabolites.

Fungi are an important and prolific source of secondary metabolites (SMs) with diverse chemical structures and a wide array of biological properties. In the past two decades, however, the number of new fungal SMs by traditional monoculture method had been greatly decreasing. Fortunately, a growing number of studies have shown that co-culture strategy is an effective approach to awakening silent SM biosynthetic gene clusters (BGCs) in fungal strains to produce cryptic SMs. To enrich our knowledge of this approach and better exploit fungal biosynthetic potential for new drug discovery, this review comprehensively summarizes all fungal co-culture methods and their derived new SMs as well as bioactivities on the basis of an extensive literature search and data analysis. Future perspective on fungal co-culture study, as well as its interaction mechanism, is supplied.