The notable characteristics of recently emerged Antibody-Drug Conjugates (ADCs) encompass the targeting of Human Epidermal growth factor Receptor 2 (HER2) through monoclonal antibodies (mAbs) and a high ratio of drug to antibody (DAR). The achievements of Kadcyla® (T-DM1) and Enhertu® (T-Dxd) have demonstrated that HER2-targeting antibodies, such as trastuzumab, have shown to be competitive in terms of efficacy and price for development. Furthermore, with the arrival of T-Dxd and Trodelvy®, high-DAR (7-8) ADCs, which differ from the moderate DAR (3-4) ADCs that were formerly regarded as conventional, are being acknowledged for their worth. Following this trend of drug development, we endeavored to develop a high-DAR ADC using a straightforward approach involving the utilization of DM1, a highly potent substance, in combination with the widely recognized trastuzumab. To achieve a high DAR, DM1 was conjugated to reduced cysteine through the simple design and synthesis of various dimaleimide linkers with differing lengths. Using LC and MS analysis, we have demonstrated that our synthesis methodology is uncomplicated and efficacious, yielding trastuzumab-based ADCs that exhibit a remarkable degree of uniformity. These ADCs have been experimentally substantiated to exert an inhibitory effect on cancer cells in vitro, thus affirming their value as noteworthy additions to the realm of ADCs.

Myotonic dystrophy type 1 (DM1) is a rare autosomal dominant genetic disorder. Although DM1 is primarily characterized by progressive muscular weakness, it exhibits many multisystemic manifestations, such as cognitive deficits, cardiac conduction abnormalities, and cataracts, as well as endocrine and reproductive issues. Additionally, the gastrointestinal (GI) tract is frequently affected, encompassing the entire digestive tract. However, the underlying causes of these GI symptoms remain uncertain, whether it is biomechanical problems of the intestine, involvement of bacterial communities, or both. The primary objective of this study is to investigate the structural changes in the gut microbiome of DM1 patients. To achieve this purpose, 35 patients with DM1 were recruited from the DM-Scope registry of the neuromuscular clinic in the Saguenay-Lac-St-Jean region of the province of Québec, Canada. Stool samples from these 35 patients, including 15 paired samples with family members living with them as controls, were collected. Subsequently, these samples were sequenced by 16S MiSeq and were analyzed with DADA2 to generate taxonomic signatures. Our analysis revealed that the DM1 status correlated with changes in gut bacterial community. Notably, there were differences in the relative abundance of Bacteroidota, Euryarchaeota, Fusobacteriota, and Cyanobacteria Phyla compared to healthy controls. However, no significant shift in gut microbiome community structure was observed between DM1 phenotypes. These findings provide valuable insights into how the gut bacterial community, in conjunction with biomechanical factors, could potentially influence the gastrointestinal tract of DM1 patients.

UNASSIGNED: Myotonic dystrophy type 1 (DM1) is a hereditary neuromuscular disorder affecting the central nervous system (CNS). Although sex differences have been explored in other neuromuscular disorders, research on this topic in DM1 remains limited. The present study aims to analyze sex differences (both the patient\'s and disease-transmitting parent\'s sex) with a focus on CNS outcomes.
UNASSIGNED: Retrospective data from 146 non-congenital DM1 patients were analyzed, including clinical, molecular, neuropsychological, and neuroradiological data. Sex and inheritance pattern differences were analyzed using t-tests, and ANOVA analyses were conducted to address the interactions.
UNASSIGNED: Overall, no significant sex differences were observed except in certain cognitive domains. However, individuals with maternal inheritance showed larger CTG expansion size, lower estimated IQs, and poorer performance on visual memory, executive functions, and language domains than those with paternal inheritance. Notably, IQ performance was independently influenced by inheritance pattern and CTG expansion.
UNASSIGNED: This study is the first to delve into sex differences in DM1 with a focus on CNS outcomes. While the results revealed the absence of a sex-specific clinic-molecular profile, more substantial CNS differences were observed between patients with maternal and paternal inheritance patterns. The hypothetical existence of genomic imprinting and its potential mechanism are discussed. These findings hold potential implications for aiding clinical management by improving genetic counseling and predicting disease severity and prognosis.

A critical parameter during the development of protein therapeutics is to endow them with suitable pharmacokinetic and pharmacodynamic properties. Small protein drugs are quickly eliminated by kidney filtration, and in vivo half-life extension is therefore often desired. Here, different half-life extension technologies were studied where PAS polypeptides (PAS300, PAS600), XTEN polypeptides (XTEN288, XTEN576), and an albumin binding domain (ABD) were compared for half-life extension of an anti-human epidermal growth factor receptor 2 (HER2) affibody-drug conjugate. The results showed that extension with the PAS or XTEN polypeptides or the addition of the ABD lowered the affinity for HER2 to some extent but did not negatively affect the cytotoxic potential. The half-lives in mice ranged from 7.3 h for the construct including PAS300 to 11.6 h for the construct including PAS600. The highest absolute tumor uptake was found for the construct including the ABD, which was 60 to 160% higher than the PASylated or XTENylated constructs, even though it did not have the longest half-life (9.0 h). A comparison of the tumor-to-normal-organ ratios showed the best overall performance of the ABD-fused construct. In conclusion, PASylation, XTENylation, and the addition of an ABD are viable strategies for half-life extension of affibody-drug conjugates, with the best performance observed for the construct including the ABD.

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Diabetes mellitus (DM) is a public health concern in Brazil, with deleterious effects on quality of life and increasing mortality rates. The prevalence of diabetes in Brazil is on the rise, and it is imperative to understand its effects on mortality rates in the last two decades in order to effectively mitigate the detrimental impact of diabetes on public health. This study aims to analyze mortality trends related to diabetes in Brazil from 2000 to 2021, encompassing both type 1 and type 2 diabetes, across sex and various age cohorts. Using joinpoint regression analysis, temporal trends in Brazil were assessed, while also incorporating findings from previous studies and considering potential influencing factors, such as government initiatives and cuts in healthcare investment. The study revealed a general upward trend in mortality rates associated with DM1 and DM2 over the study period, in both males and females, with men showing a higher AAPC (average annual percent change), which translated into significantly increased mortality difference at the end of the study. Additionally, it revealed elevated mortality values for extreme age groups in the age cohorts studied, with the exception of middle-aged cohort groups in DM2, which showed an expected higher APC (annual percent change), considering the age of highest incidence of DM2 in those age groups. This comprehensive analysis provides critical insights into the escalating impact of diabetes on mortality rates in Brazil and highlights the urgent need for healthcare strategies. It is expected that the increased prevalence of diabetes in the Brazilian population adds an additional economic burden to healthcare expenditure by the Brazilian government, further worsening the health disparities among different social groups. Unless several political decisions to reduce healthcare expenditure are reversed, greater difficulties in accessing treatments will be detrimental for vulnerable social groups in Brazil. By understanding the nuanced patterns of diabetes-related mortality, healthcare providers and policymakers can allocate resources effectively and implement tailored interventions to better address diabetes in Brazil.

Gastrointestinal and urological symptoms are frequently reported by people with myotonic dystrophy type 1 (DM1) but have remained understudied. In a cross-sectional study, frequency, nature, treatment and impact of gastrointestinal and urological symptoms in children with DM1 aged 5-18 years were assessed. We included 58 children (30 males, 28 females) with a mean age of 13 years; 74.1 % reported at least one gastrointestinal symptom. Abdominal pain was the most frequently reported symptom (51.7 %), followed by dysphagia (41.8 %), diarrhoea (36.2 %), encopresis (36.0 %), constipation (32.7 %), bloating and flatulence (both 25.9 %). The most frequently reported urological symptoms were difficulty with toilet training (59.3 %), urinary incontinence (22.0 %), enuresis nocturna (10.3 %) and voiding (23.5 % hesitancy, 4.8 % intermittency and 13.8 % dysuria). The majority considered urological and gastrointestinal symptoms to have a negative influence on their daily life; 22.4 % of parents reported severe influence on daily family life (shame, social restrictions, school absence and concerns for their children\'s future). Considering the high prevalence of urological and gastrointestinal symptoms in children with DM1 and their influence on daily life it is key to correctly recognize, diagnose and treat these symptoms. We recommend screening for gastrointestinal and urological symptoms in the standard of care for children with DM1.

Central nervous system dysfunction is characteristic of patients with myotonic dystrophy type 1 (DM1). Although no consensus exists regarding the exact cognitive profile of these patients, executive dysfunction has been suggested to play a role. Due to the impact of executive functions on daily performance, this study aimed to describe executive functioning in an ecological manner and to analyze its impact - and that of other clinical variables - on the functional performance of DM1 patients. A Virtual Reality executive functioning test (Nesplora Ice Cream), the Wechsler Adult Intelligence Scale-Fourth Edition, and self-report questionnaires (AES, FSS, ESS and LIFE-H) were administered to 20 patients. Statistical analyses included correlation and multiple regression analyses to analyze the best predictors of daily performance. DM1 patients did not show major difficulties in the executive functioning tasks or in their overall performance on daily habits. However, both cold and hot executive functions still seem necessary for the correct accomplishment of life habits, since planning and level of apathy explained 47.6% of the total variance of daily functioning. This was the first study to assess executive functions in DM1 using Virtual Reality, and our findings open a debate about their actual impairment in this population.

Among the cognitive difficulties shown by myotonic dystrophy type 1 (DM1) patients, visuoconstructional impairment - specifically measured with the Rey-Osterrieth Complex Figure Test (RCFT) - is particularly notable. This study aimed to analyze the performance of DM1 patients and healthy controls (HC) in the RCFT, using different correction systems in order to explore the cognitive processes underlying the poor performance and its associations with other signs and symptoms.
Data from 66 DM1 patients and 68 HC were included in this study. All participants had a comprehensive neuropsychological assessment, including the RCFT, which was scored using both the traditional Osterrieth and the Boston Qualitative Scoring System (BQSS) procedures. ANCOVA and Spearman\'s correlation analyses were conducted.
DM1 Patients obtained significantly poorer scores than HC on the RCFT using both correction systems. Regarding BQSS, patients performed worse than HC in both main indexes (Copy Presence Accuracy-CPA and Organization-ORG), and specifically on scores of Configural accuracy, Planning, and Perseveration. Both main indexes - but especially CPA - showed significant and strong correlations with several clinical and cognitive variables.
Both visuoconstruction and organizational impairments underlie the poor RCFT performance in DM1. Moreover, visuoconstruction ability appears to be sensitive to the clinical hallmarks of DM1 patients. The RCFT is proposed as a gold standard in DM1 assessment and the merits of using alternative scoring systems are discussed.

Small-molecule drug conjugates (SMDCs) are compounds in which a therapeutic payload is conjugated to a targeting vector, for specific delivery to the tumor site. This promising approach can be translated to the treatment of prostate cancer by selecting a targeting vector which binds to the prostate-specific membrane antigen (PSMA). Moreover, the addition of a bifunctional chelator to the molecule allows for the use of both diagnostic and therapeutic radionuclides. In this way, the distribution of the SMDC in the body can be monitored, and combination therapy regimes can be implemented. We combined a glutamate-urea-lysine vector to the cytotoxic agent DM1 and a DOTA chelator via an optimized linker to obtain the theranostic SMDC (T-SMDC) ePSMA-DM1. ePSMA-DM1 retained a high binding affinity to PSMA and demonstrated PSMA-specific uptake in cells. Glutathione stability assays showed that the half-life of the T-SMDC in a reducing environment was 2 h, and full drug release was obtained after 6 h. Moreover, 100 nM of ePSMA-DM1 reduced the cell viability of the human PSMA-positive LS174T cells by >85% after 72 h of incubation, which was comparable to a 10-fold higher dose of free DM1. [111In]In-ePSMA-DM1 and [177Lu]Lu-ePSMA-DM1 were both obtained in high radiochemical yields and purities (>95%), with >90% stability in PBS and >80% stability in mouse serum for up to 24 h post incubation at 37 °C. SPECT/CT imaging studies allowed for a faint tumor visualization of [111In]In-ePSMA-DM1 at 1 h p.i., and the ex vivo biodistribution showed tumor uptake (2.39 ± 0.29% ID/g) at 1 h p.i., with the compound retained in the tumor for up to 24 h. Therefore, ePSMA-DM1 is a promising T-SMDC candidate for prostate cancer, and the data obtained so far warrant further investigations, such as therapeutic experiments, after further optimization.