Clinical Management of Patients With Relapsed/Refractory Multiple Myeloma Treated With Talquetamab.

BACKGROUND: Talquetamab is a bispecific antibody targeting the multiple myeloma-associated antigen G protein-coupled receptor family C group 5 member D (GPRC5D). In the phase 1/2 MonumenTAL-1 trial (NCT03399799/NCT04634552), overall responses rates were > 71% in patients with triple-class exposed relapsed/refractory multiple myeloma (RRMM). Due to the distribution of the target antigen, a unique pattern of GPRC5D-associated adverse events (AEs) was observed, together with T-cell redirection-associated AEs. Management strategies for talquetamab-associated AEs are described. DISCUSSION: GPRC5D-associated AEs included dermatologic (rash, nonrash, and nail toxicities) and oral AEs (dysgeusia, dysphagia, and dry mouth). The incidence of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were consistent with other T-cell redirection therapies. The incidence of high-grade infections was lower than observed with B-cell maturation antigen-targeting bispecific antibodies, with less frequent use of intravenous immunoglobulin required. GPRC5D-associated AEs were mostly low grade and led to few discontinuations. Skin toxicities were managed with emollients, topical corticosteroids, and oral corticosteroids (for high-grade, persistent, or AEs that progress). Nail toxicities were commonly managed with emollients. Based on investigator experience, dose modification may be effective for controlling oral events. Observation for potential weight changes is required. Infections were managed per standard of care. CRS and ICANS were effectively managed, consistent with other trials of T-cell redirection therapies. CONCLUSION: Although talquetamab had a distinct safety profile, AEs were considered clinically manageable and mostly low grade. With appropriate education and support, health care practitioners can ensure patients with RRMM maintain quality of life and treatment adherence.

A Pfs48/45-based vaccine to block Plasmodium falciparum transmission: phase 1, open-label, clinical trial.

BACKGROUND: The stalling global progress in malaria control highlights the need for novel tools for malaria elimination, including transmission-blocking vaccines. Transmission-blocking vaccines aim to induce human antibodies that block parasite development in the mosquito and mosquitoes becoming infectious. The Pfs48/45 protein is a leading Plasmodium falciparum transmission-blocking vaccine candidate. The R0.6C fusion protein, consisting of Pfs48/45 domain 3 (6C) and the N-terminal region of P. falciparum glutamate-rich protein (R0), has previously been produced in Lactococcus lactis and elicited functional antibodies in rodents. Here, we assess the safety and transmission-reducing efficacy of R0.6C adsorbed to aluminium hydroxide with and without Matrix-M™ adjuvant in humans. METHODS: In this first-in-human, open-label clinical trial, malaria-naïve adults, aged 18-55 years, were recruited at the Radboudumc in Nijmegen, the Netherlands. Participants received four intramuscular vaccinations on days 0, 28, 56 and 168 with either 30 µg or 100 µg of R0.6C and were randomised for the allocation of one of the two different adjuvant combinations: aluminium hydroxide alone, or aluminium hydroxide combined with Matrix-M1™ adjuvant. Adverse events were recorded from inclusion until 84 days after the fourth vaccination. Anti-R0.6C and anti-6C IgG titres were measured by enzyme-linked immunosorbent assay. Transmission-reducing activity of participants' serum and purified vaccine-specific immunoglobulin G was assessed by standard membrane feeding assays using laboratory-reared Anopheles stephensi mosquitoes and cultured P. falciparum gametocytes. RESULTS: Thirty-one participants completed four vaccinations and were included in the analysis. Administration of all doses was safe and well-tolerated, with one related grade 3 adverse event (transient fever) and no serious adverse events occurring. Anti-R0.6C and anti-6C IgG titres were similar between the 30 and 100 µg R0.6C arms, but higher in Matrix-M1™ arms. Neat participant sera did not induce significant transmission-reducing activity in mosquito feeding experiments, but concentrated vaccine-specific IgGs purified from sera collected two weeks after the fourth vaccination achieved up to 99% transmission-reducing activity. CONCLUSIONS: R0.6C/aluminium hydroxide with or without Matrix-M1™ is safe, immunogenic and induces functional Pfs48/45-specific transmission-blocking antibodies, albeit at insufficient serum concentrations to result in transmission reduction by neat serum. Future work should focus on identifying alternative vaccine formulations or regimens that enhance functional antibody responses. TRIAL REGISTRATION: The trial is registered with ClinicalTrials.gov under identifier NCT04862416.

Results from the UNITED study: a multicenter study validating the prognostic effect of the tumor-stroma ratio in colon cancer.

BACKGROUND: The TNM (tumor-node-metastasis) Evaluation Committee of Union for International Cancer Control (UICC) and College of American Pathologists (CAP) recommended to prospectively validate the cost-effective and robust tumor-stroma ratio (TSR) as an independent prognostic parameter, since high intratumor stromal percentages have previously predicted poor patient-related outcomes. PATIENTS AND METHODS: The 'Uniform Noting for International application of Tumor-stroma ratio as Easy Diagnostic tool' (UNITED) study enrolled patients in 27 participating centers in 12 countries worldwide. The TSR, categorized as stroma-high (>50%) or stroma-low (≤50%), was scored through standardized microscopic assessment by certified pathologists, and effect on disease-free survival (DFS) was evaluated with 3-year median follow-up. Secondary endpoints were benefit assessment of adjuvant chemotherapy (ACT) and overall survival (OS). RESULTS: A total of 1537 patients were included, with 1388 eligible stage II/III patients curatively operated between 2015 and 2021. DFS was significantly shorter in stroma-high (n = 428) than in stroma-low patients (n = 960) (3-year rates 70% versus 83%; P < 0.001). In multivariate analysis, TSR remained an independent prognosticator for DFS (P < 0.001, hazard ratio 1.49, 95% confidence interval 1.17-1.90). As secondary outcome, DFS was also worse in stage II and III stroma-high patients despite adjuvant treatment (3-year rates stage II 73% versus 92% and stage III 66% versus 80%; P = 0.008 and P = 0.011, respectively). In stage II patients not receiving ACT (n = 322), the TSR outperformed the American Society of Clinical Oncology (ASCO) criteria in identifying patients at risk of events (event rate 21% versus 9%), with a higher discriminatory 3-year DFS rate (stroma-high 80% versus ASCO high risk 91%). A trend toward worse 5-year OS in stroma-high was noticeable (74% versus 83% stroma-low; P = 0.102). CONCLUSION: The multicenter UNITED study unequivocally validates the TSR as an independent prognosticator, confirming worse outcomes in stroma-high patients. The TSR improved current selection criteria for patients at risk of events, and stroma-high patients potentially experienced chemotherapy resistance. TSR implementation in pathology diagnostics and international guidelines is highly recommended as aid in personalized treatment.

Treatment of task-specific dystonia in sports: A systematic review.

Introduction: Task specific dystonia is a movement disorder only affecting a highly practiced skill and is found in a broad set of expert movements including in sports. Despite affecting many sports, there is no comprehensive review of treatment options, which is in contrast to better studied forms of task specific dystonia in musicians and writers. For this reason, studies involving an intervention to treat task specific dystonia in sports were systematically reviewed, with special attention for the quality of outcome measures. Methods: The PICO systematic search strategy was employed on task-specific dystonia, and all synonyms. Inclusion criteria were peer reviewed published studies pertaining to sports, studies with a measurement and/or intervention in TSD, all in English. We excluded abstracts, expert opinions, narrative review articles, unpublished studies, dissertations and studies exclusively relating to choking. We included case reports, case studies and case-control studies. Results: In April 2022 Pubmed, Embase, Web of Science, and Psychinfo were searched. Of the 7000 articles identified, 31 were included that described psychological and invasive and/or pharmacological interventions. There was a lack of formal standardized outcome measures in studies resulting in low quality evidence for the effectiveness of treatment options. A descriptive synthesis showed emotional regulation was effective, but was exclusively tried in golfers. Interventions like botulinum toxin or pharmacology had a similar effectiveness compared to studies in musicians dystonia, however there was almost no formal evidence for these treatments. Conclusion: The quality of studies was low with a lack of standardized outcome measures. Future studies with larger cohorts and quantitative outcome measures are needed to improve understanding of treatments for task specific dystonia in athletes.

Oral health assessment in institutionalized elderly: a scoping review.

When elderly become frail and in need for complex care, they can no longer live independently at home and may be admitted to nursing homes. Various studies have shown that oral health in this population is remarkably poor, which may lead to distressing situations and impacts quality of life. A variety of definitions or descriptions for oral health is used. Without a uniform parameter, it is impossible to determine whether oral health in institutionalized elderly is actually improving or deteriorating over time, as well as the effect of (preventive) interventions. In search for an adequate and clinically applicable parameter to determine oral health in this specific patient group, this scoping review aims to give an overview of the currently used parameters for determining oral health in institutionalized elderly. Ninety different parameters were identified, and 50 parameters were solely used by one study. Only 4 parameters were frequently used (in > 20 studies). The relevance of these parameters for this specific patient group is discussed. To aid the planning and commissioning of future research and patient care, there is an urgent need for an adequate and uniform parameter for oral health determination in institutionalized elderly.

The increasing burden of testicular seminomas and non-seminomas in adolescents and young adults (AYAs): incidence, treatment, disease-specific survival and mortality trends in the Netherlands between 1989 and 2019.

BACKGROUND: Testicular cancer incidence among adolescents and young adults (AYAs, aged 18-39 years at diagnosis) is increasing worldwide and most patients will survive the initial disease. Still, detailed epidemiological information about testicular cancer among AYAs is scarce. This study aimed to provide a detailed overview of testicular cancer trends in incidence, treatment, long-term relative survival and mortality by histological subtype among AYAs diagnosed in the Netherlands between 1989 and 2019. MATERIALS AND METHODS: Data of all malignant testicular cancers (ICD-code C62) were extracted from the Netherlands Cancer Registry. Mortality data were retrieved from Statistics Netherlands. European age-standardized incidence and mortality rates with average annual percentage change statistics and relative survival estimates up to 20 years of follow-up were calculated. RESULTS: A total of 12 528 testicular cancers were diagnosed between 1989 and 2019. Comparing 1989-1999 to 2010-2019, the incidence increased from 4.4 to 11.4 for seminomas and from 5.7 to 11.1 per 100 000 person-years for non-seminomas. Rising trends were most prominent for localized disease. Radiotherapy use in localized testicular seminomas declined from 78% in 1989-1993 to 5% in 2015-2019. Meanwhile, there was a slight increase in chemotherapy use. Most AYAs with localized seminomas and non-seminomas received active surveillance only (>80%). Overall, relative survival estimates remained well above 90% even at 20 years of follow-up for both seminomas and non-seminomas. Mortality rates declined from 0.5 to 0.4 per 100 000 person-years between 1989-1999 and 2010-2019. CONCLUSIONS: The incidence of seminoma and non-seminoma testicular cancers significantly increased in AYAs in the Netherlands between 1989 and 2019. There was a shift towards less-aggressive treatment regimens without negative survival effects. Relative survival estimates remained well above 90% at 20 years of follow-up in most cases. Testicular cancer mortality was already low, but has improved further over time, which makes survivorship care an important issue for these young adults.

Changes in perceived peripersonal space following the rubber hand illusion.

Peripersonal space (PPS), the region immediately surrounding the body is essential for bodily protection and goal directed action. Previous studies have suggested that the PPS is anchored to one's own body and in the current study we investigated whether the PPS could be modulated by changes in perceived body ownership. While theoretically important, this anchoring can also have implications for patients with altered body perception. The rubber hand illusion (RHI) is a way to manipulate body ownership. We hypothesized that after induction of a left hand RHI, the perceived space around the body shifts to the right. Sixty-five participants performed a landmark task before and after a left hand RHI. In the landmark task, participants had to determine whether a vertical landmark line was left or right from the center of a horizontal screen. One group of the participants was exposed to synchronous stroking, the other group experienced asynchronous stroking. Results showed a shift in space to the right (e.g. away from the own arm), but only for the 'synchronous stroking' group. These results suggest that the relevant action space becomes linked to the fake hand. Critically, subjective ownership experience did not correlate with this shift, but proprioceptive drift did. This suggests that multisensory integration of bodily information drives this shift in space around the body and not feelings of ownership.

[Whether or not to remove root remnants in frail older adults?] / Wel of niet wortelresten verwijderen bij kwetsbare ouderen?

Many frail older adults have a poor oral health: unrestorable broken teeth and root remnants with open root canals, commonly associated with periapical and periodontal inflammation, are often seen. Improving oral health in this growing group of frail older adults is a considerable challenge for dental care professionals. Dentists are often uncertain how to deal with root remnants and unrestorable broken teeth in psychogeriatric and/or medically compromised frail older adults. Decisions about the extraction or retention of root remnants should not only be made on the basis of preventing pain and inflammation, but also on the course of disease, life expectancy, cooperation, laws and regulations and other factors that are an issue in geriatric patients but not in regular (healthy) patients. To help oral health care professionals in their treatment choice for this complex patient group, a decision tree was developed in which both root and patient-related factors were included.

Small bowel intussusception caused by a metastatic testicular germ cell tumour.

SUMMARY: Intussusception from a testicular germ cell tumour is extremely rare. Metastatic gastrointestinal implants outgrow their blood supply leading to central necrosis. This results in erosions and ulcerations, which can be visualised as submucosal polypoid masses. These masses can then serve as a lead point for intussusception. We report a case of a 25-year-old patient with small bowel obstruction due to an intussuscepted choriocarcinoma in the absence of any other apparent retroperitoneal disease. Urologists must exclude gastrointestinal tract (GIT) involvement in testicular cancers, and similarly, surgeons need to exclude testicular tumours in young men with unexplained GIT haemorrhage, bowel obstruction or intussusception.

[Lifetime dental care: treatment for periodontally affected elderly]. / Levensloopbestendig behandelen van de oudere met parodontitis.

Although many elderly remain healthy to an advanced age, apparently healthy and robust elderly can quickly become frail as a result of physical or psychological events. With frailty, oral health can quickly deteriorate and treatment is often difficult, with possible consequences for general health and quality of life. To prevent treatment dilemma's at an advanced age, it is advisable to think ahead when making a treatment plan for older patients and to aim for a surveyable oral situation, so in case of illness or care dependency, oral health can be maintained relatively easily. This so-called 'lifetime' dental treatment plan takes into account the various areas of frailty (physical, psychological and social), is predictable and can be modified, and takes life expectancy and general health into consideration. Lifetime dental treatment for the elderly, specifically the periodontally affected, has as yet rarely been discussed in the literature. This article represents a view of such treatment on the basis of clinical expertise.

Time-lapse imaging of human embryos fertilized with testicular sperm reveals an impact on the first embryonic cell cycle.

Testicular sperm is increasingly used during in vitro fertilization treatment. Testicular sperm has the ability to fertilize the oocyte after intracytoplasmic sperm injection (ICSI), but they have not undergone maturation during epididymal transport. Testicular sperm differs from ejaculated sperm in terms of chromatin maturity, incidence of DNA damage, and RNA content. It is not fully understood what the biological impact is of using testicular sperm, on fertilization, preimplantation embryo development, and postimplantation development. Our goal was to investigate differences in human preimplantation embryo development after ICSI using testicular sperm (TESE-ICSI) and ejaculated sperm. We used time-lapse embryo culture to study these possible differences. Embryos (n = 639) originating from 208 couples undergoing TESE-ICSI treatment were studied and compared to embryos (n = 866) originating from 243 couples undergoing ICSI treatment with ejaculated sperm. Using statistical analysis with linear mixed models, we observed that pronuclei appeared 0.55 h earlier in TESE-ICSI embryos, after which the pronuclear stage lasted 0.55 h longer. Also, significantly more TESE-ICSI embryos showed direct unequal cleavage from the 1-cell stage to the 3-cell stage. TESE-ICSI embryos proceeded faster through the cleavage divisions to the 5- and the 6-cell stage, but this effect disappeared when we adjusted our model for maternal factors. In conclusion, sperm origin affects embryo development during the first embryonic cell cycle, but not developmental kinetics to the 8-cell stage. Our results provide insight into the biological differences between testicular and ejaculated sperm and their impact during human fertilization.

Hypoxaemia during tracheal intubation in patients with hypertensive disorders of pregnancy: analysis of data from an obstetric airway management registry.

BACKGROUND: In South Africa, hypertensive disorders of pregnancy are the leading cause of maternal mortality. More than 50% of anaesthesia-related maternal deaths are attributed to complications of airway management. We compared the prevalence and risk factors for hypoxaemia during induction of general anaesthesia in parturients with and without hypertensive disorders of pregnancy. We hypothesised that hypertensive disorders of pregnancy are associated with desaturation during tracheal intubation. METHODS: Data from 402 cases in a multicentre obstetric airway management registry were analysed. The prevalence of peri-induction hypoxaemia (SpO2 <90%) was compared in patients with and without hypertensive disorders of pregnancy. Quantile regression of SpO2 nadir was performed to identify confounding variables associated with, and mediators of, hypoxaemia. RESULTS: In the cohort of 402 cases, hypoxaemia occurred in 19% with and 9% without hypertension (estimated risk difference, 10%; 95% CI 2% to 17%; P=0.005). Quantile regression demonstrated a lower SpO2 nadir associated with hypertensive disorders of pregnancy as body mass index increased. Room-air oxygen saturation, Mallampati grade, and number of intubation attempts were associated with the relationship. CONCLUSIONS: Clinically significant oxygen desaturation during airway management occurred twice as often in patients with hypertensive disorders of pregnancy, compounded by increasing body mass index. Intermediary factors in the pathway from hypertension to hypoxaemia were also identified.

[Clinical characteristics of sexually abused individuals with borderline intellectual functioning or mild intellectual disability: an overview of the literature]. / Klinische kenmerken van seksueel misbruikte mensen met een lichte verstandelijke beperking: een literatuuroverzicht.

BACKGROUND: Sexual abuse in individuals with (above) average iq is associated with a wide range of behavioural and psychological clinical characteristics, including characteristics regarding body experience. However, research on the clinical characteristics of sexually abused individuals with borderline intellectual functioning or mild intellectual disability (bif-mid) is scarce. OBJECTIVE To provide an overview of the literature on the clinical characteristics of sexually abused individuals with bif-mid.
METHOD: PubMed, Embase, PsycInfo, cinahl, Cochrane Library and Web of Science were searched for relevant publications using terms related to 'intellectual disability' and 'sexual abuse'.
RESULTS: Seven studies were included. The studies in question mostly reported behavioural and psychological characteristics such as challenging behaviour, sexualised behaviour or posttraumatic stress, anxiety or depressive symptoms associated with sexual abuse in individuals with bif-mid. None of the studies reported problems regarding body experience. CONCLUSIONS Sexual abuse in individuals with bif-mid is associated with a broad range of behavioural and psychological characteristics similar to that of individuals with (above) average iq. Whether sexually abused individuals with bif-mid have similar problems in body experience as sexually abused individuals with (higher than) average iq needs to be investigated.

Diabetes mellitus and COVID-19: A review and management guidance for South Africa.

This article reviews the association between diabetes mellitus (DM) and COVID-19. We report on the convergence of infectious diseases such as coronavirus infections and non-communicable diseases including DM. The mechanisms for the interaction between COVID-19 and DM are explored, and suggestions for the management of DM in patients with COVID-19 in South Africa are offered.

Brassica napus and Brassica juncea extruded-expelled cake and solvent-extracted meal as feedstuffs for laying hens: Lay performance, egg quality, and nutrient digestibility.

Two experiments evaluated feeding Brassica (B.) napus (canola) or B. juncea co-products to brown-shelled egg laying hens. In Exp. 1, diets including 20% B. napus or B. juncea extruded-expelled cakes (NC, JC) or solvent-extracted meals (NM, JM) compared to a control diet with no Brassica co-products, were fed to 120 hens (4 hens/cage, n = 6) for 36 wk. In Exp. 2, DM, gross energy, CP and amino acid (AA) retention/digestibility was determined by feeding diets containing 30% B. napus or B. juncea cakes or meals and basal diet to 240 hens (8 hens/pair of cages, n = 6) for 7 d. Cakes averaged 40 g/kg lower moisture, 28 g/kg lower CP, and 84 g/kg greater fat content compared with meals. In Exp. 1, there was no effect of diet on lay percentage or BW throughout the experiment. Feed consumption was 3.5 g/d lower in layers fed JM compared with controls and egg: feed was reduced by 14 mg egg/g feed in layers fed JC (P < 0.01). Although eggs from layers fed NM were 0.7 g heavier than controls, eggs from layers fed NC, JM or JC were 1.4 g lighter than controls (P < 0.01). Eggs from layers fed Brassica diets contained a greater proportion (1.6%-points) of monounsaturated fatty acids compared with controls (P < 0.01). Eggs from layers fed B. juncea had a relatively greater proportion (0.2%-points) of C18:3 (n3) compared with those of layers fed B. napus diets (P < 0.01). Feeding Brassica diets reduced digestibility of DM (5%-points), gross energy (7%-points) and CP (4%-points) vs. basal (P < 0.01). The digestibility of indispensable AA except tryptophan, was reduced feeding Brassica diets vs. basal (P < 0.01). We concluded that feeding B. napus and B. juncea extruded-expelled cakes and solvent-extracted meal at 20% of diets to hens supported acceptable lay performance and egg quality over a 36 wk production cycle. Digestibility data indicated that indispensable AA in Brassica co-products had moderately high (75 to 85%) apparent ileal digestibility.

Measurement of anti-TSH receptor antibodies: what is the correct cut-off value?

BACKGROUND: Autoantibodies against the thyroid stimulating hormone receptor, thyrotropin receptor autoantibodies (TRAb) are diagnostic for Graves' disease and can be measured by different methods. As antibody concentrations are not comparable between methods, appropriate cut-off values need to be established for every single method. For a third-generation TRAb assay (Phadia, Thermofisher), the manufacturer determined the cut-off value in a study population consisting of Graves' disease (both newly diagnosed and patients under treatment) and non-Graves' disease patients. The aim of this study was to verify whether this cut-off value holds true in our population. METHODS: Retrospective analysis was performed on TRAb measurements collected over a period of six months from all patients referred for TRAb testing. For our study, we included patients that were newly diagnosed with hyperthyroidism including Graves' disease, multinodular goitre, toxic adenoma, and thyroiditis. Furthermore, we included Graves' patients that were under treatment at the time of TRAb measurement. RESULTS: Whereas all patients with Graves' disease had positive TRAb, few patients with multinodular goitre, toxic adenoma, and thyroiditis scored positive for TRAb. ROC curve analysis revealed a cut-off value of 4.5 IU/l (compared to 3.3 IU/l established by the manufacturer). Newly diagnosed Graves' patients had higher TRAb concentrations compared to patients under treatment. CONCLUSION: The cut-off value of this immunoassay should probably be set higher in untreated Graves' patients than proposed by the manufacturer as the cut-off value should be determined in a study population excluding Graves' patients under treatment. The overall clinical picture remains crucial in the diagnosis of Graves' disease.

Career development in fragment-based drug discovery.

The pharmaceutical industry is highly reliant on researchers who not only possess the technical knowledge but also the professional skills to collaborate in drug development. To prepare future practitioners to thrive in this interdisciplinary environment, Innovative Training Networks (ITNs) have become increasingly important in doctoral training. In this piece, we explore the benefits of these ITNs in training future practitioners in drug discovery. Through a bibliometric review, we find that the top researchers in fragment-based drug discovery have a high degree of collaboration and mobility across institutes. We then investigate which aspects of the ITN training program enable PhD students to gain these skills. We find that secondments, the short-term stays that students have in partner research institutes, are useful in preparing students to have both broad knowledge of drug discovery and specialization in their field of interest. Aside from imparting technical skills, we find that the collaborative environment in ITNs enables students to communicate better and to work effectively in teams. Doctoral students benefit by being exposed to relevant experiences that they can later apply as they navigate through the complex web of relationships and competencies in the industry. We conclude by recommending best practices to further improve ITNs in the training of future practitioners.

Diabetes mellitus and COVID-19: A review and management guidance for South Africa

This article reviews the association between diabetes mellitus (DM) and COVID-19. We report on the convergence of infectious diseases such as coronavirus infections and non-communicable diseases including DM. The mechanisms for the interaction between COVID-19 and DM are explored, and suggestions for the management of DM in patients with COVID-19 in South Africa are offered

Cellular origin of microRNA-371a-3p in healthy males based on systematic urogenital tract tissue evaluation.

BACKGROUND: The microRNA-371a-3p (miR-371a-3p) has been reported to be an informative liquid biopsy (serum and plasma) molecular biomarker for both diagnosis and follow-up of patients with a malignant (testicular) germ cell tumor ((T)GCT). It is expressed in all histological cancer elements, with the exception of mature teratoma. However, normal testis, semen, and serum of males with a disrupted testicular integrity without a TGCT may contain miR-371a-3p levels above threshold, of which the cellular origin is unknown. OBJECTIVES: Therefore, a series of relevant tissues (frozen and formalin-fixed paraffin-embedded (FFPE), when available) from the complete male urogenital tract (i.e., kidney to urethra and testis to urethra) and semen was investigated for miR-371a-3p levels using targeted quantitative RT-PCR (qRT-PCR). MATERIALS AND METHODS: In total, semen of males with normospermia (n = 11) and oligospermia (n = 3) was investigated, as well as 88 samples derived from 32 different patients. The samples represented one set of tissues related to the entire male urogenital tract (11 anatomical locations), three sets for 10 locations, and four sets for six locations. RESULTS: All testis parenchyma (n = 17) cases showed low miR-371a-3p levels. Eight out of 14 (57%) semen samples showed detectable miR-371a-3p levels, irrespective of the amount of motile spermatozoa, but related to sperm concentration and matched Johnsen score (Spearman's rho correlation coefficient 0.849 and 0.871, p = 0.000, respectively). In all other tissues investigated, miR-371a-3p could not be detected. DISCUSSION: This study demonstrates that the miR-371a-3p in healthy adult males is solely derived from the germ cell compartment. CONCLUSIONS: The observation is important in the context of applying miR-371a-3p as molecular liquid biopsy biomarker for diagnosis and follow-up of patients with malignant (T)GCT. Moreover, miR-371a-3p might be an informative seminal biomarker for testicular germ cell composition.

Structure-based exploration and pharmacological evaluation of N-substituted piperidin-4-yl-methanamine CXCR4 chemokine receptor antagonists.

Using the available structural information of the chemokine receptor CXCR4, we present hit finding and hit exploration studies that make use of virtual fragment screening, design, synthesis and structure-activity relationship (SAR) studies. Fragment 2 was identified as virtual screening hit and used as a starting point for the exploration of 31 N-substituted piperidin-4-yl-methanamine derivatives to investigate and improve the interactions with the CXCR4 binding site. Additionally, subtle structural ligand changes lead to distinct interactions with CXCR4 resulting in a full to partial displacement of CXCL12 binding and competitive and/or non-competitive antagonism. Three-dimensional quantitative structure-activity relationship (3D-QSAR) and binding model studies were used to identify important hydrophobic interactions that determine binding affinity and indicate key ligand-receptor interactions.