Electroless Ionization Mass Spectrometry Using a Compact Electrokinetic Ionization Source.

We introduce a new ionization technique for compact, portable mass spectrometers. It consists of a syringe with sample liquid capped by a self-ionizing spray nozzle containing a microfabricated nozzle chip. Interaction of the sample liquid with the nozzle wall results in electrical charging without the need for electronics. Elaborate cleaning procedures are redundant when disposable syringes and mass-fabricated spray nozzles are used. This self-named electroless spray ionization (ELI) technique shows comparable performance to conventional ionization techniques. In contrast to commonly used electrospray ionization, ELI exhibits excellent ionization efficiency for low-conductive solutions such as water or acetonitrile. Due to its compact size and the absence of high-voltage electronics, it can also be readily integrated in other ionization sources. Besides reviewing the main properties of ELI, we showcase the technique's potential for two on-site, ambient mass spectroscopy applications: perfume fingerprinting and fast screening of fungicides on citrus fruits.

The effect of colpectomy on lower urinary tract function in transgender men.

Background: In transgender men, effects of colpectomy on voiding function are unknown, except for the incidence rates of urinary tract infections and urinary retention. Aims: To provide insight into the effect of colpectomy on Lower Urinary Tract Function (LUTF) in transgender men. Methods: A retrospective chart review was conducted among transgender men who underwent colpectomy between January 2018 and October 2020. Primary outcomes were objective and subjective changes in voiding. Secondary outcomes were transurethral catheterization length and the need for clean intermittent self-catheterization (CISC). Results: Of 132 men, 89 (67%) underwent Robot-assisted Laparoscopic Colpectomy (RaLC) and 43 (33%) Vaginal Colpectomy (VC). Maximum flow rate on uroflowmetry decreased following RaLC (mean of 29.1 vs. 38.3 mL/s, p = 0.002) and VC (mean of 29.2 vs. 40.3 mL/s, p < 0.001) after a median of four months postoperatively. An increase in total International Prostate Symptom Score was seen more frequently following VC compared to RaLC. Subjective changes were indicated by 39%, more often by men who underwent VC, of which the majority improved during the first months postoperatively. Trial without catheter (TWOC) on the first postoperative day was more successful after RaLC (79/89, 89%) than VC (24/43, 56%). Secondary TWOC was successful in 22/132 (17%) patients after a median of eight days postoperatively. In 5/132 (4%) men (three VC and two RaLC), temporary CISC was necessary for a period ranging from 5 to 21 days. The last 2/132 (2%) men after RaLC were still performing CISC at end of follow-up. Eventually, 5% (two VC and four RaLC) had to refrain from genital gender-affirming surgery with urethral lengthening due to voiding dysfunction. Discussion: After colpectomy, most objective and subjective worsening in LUTF is of a temporary nature, however, 5% had to refrain from genital gender-affirming surgery with urethral lengthening due to persistent voiding dysfunction, despite the desire to void while standing.

Comparison of surgical outcomes and urinary functioning after phalloplasty with versus without urethral lengthening in transgender men.

Background: Phalloplasty in transgender men is performed with or without Urethral Lengthening (UL). To create clear expectations in the choice of UL, an overview and comparison of outcomes is useful. Aims: To provide and compare surgical outcomes and urinary functioning after phalloplasty with versus without UL in transgender men. Methods: A single-center, retrospective chart review was conducted among transgender men who underwent phalloplasty with or without UL between 01-2013 and 10-2020. Primary outcomes were differences in complication and reoperation rates. Secondary outcomes were end-stages of voiding at last follow-up and differences in voiding analyses pre- and postoperatively. Results: Of 136 men, 91 (67%) underwent phalloplasty with, and 45 (33%) without UL. Wound infection (31 vs. 16%, p = 0.06) and partial flap loss (35 vs. 13%, p = 0.008) were predominately seen after UL. In the UL group, 43% urethral fistulas and 60% urethral strictures were observed, relative to one man without UL who had a urethral fistula (both p < 0.001). Meatal or perineal orifice stenosis was seen in 29% with versus 11% without UL (p = 0.02). Reoperation was needed in 81% with versus 27% without UL (p < 0.001). At follow-up, 80/91 (88%) after UL reached end-stage of voiding, with 60/80 (75%) able to void while standing and 20/80 (25%) having a definitive urethrostomy. The remaining 11/91 (12%) men were awaiting further treatment for urological complications. The men able to void while standing had a median of one reoperation (range 0-6), and a significant decrease in maximum flow rate on postoperative uroflowmetry (21.4 vs. 29.8 mL/s, p < 0.001). After phalloplasty without UL, all men had a definitive perineostomy without changes in voiding analyses. Discussion: The choice for or against UL during phalloplasty has become more relevant over the years. This comparison of surgical outcomes and urinary functioning can be useful in the shared decision-making process to come to the most suitable choice of phalloplasty.

Group A Streptococcus Vaccine Targeting the Erythrogenic Toxins SpeA and SpeB Is Safe and Immunogenic in Rabbits and Does Not Induce Antibodies Associated with Autoimmunity.

Group A streptococcus (GAS) is a global pathogen associated with significant morbidity and mortality for which there is currently no licensed vaccine. Vaccine development has been slow, mostly due to safety concerns regarding streptococcal antigens associated with autoimmunity and related complications. For a GAS vaccine to be safe, it must be ensured that the antigens used in the vaccine do not elicit an antibody response that can cross-react with host tissues. In this study, we evaluated the safety of our GAS vaccine candidate called VaxiStrep in New Zealand White rabbits. VaxiStrep is a recombinant fusion protein comprised of streptococcal pyrogenic exotoxin A (SpeA) and exotoxin B (SpeB), also known as erythrogenic toxins, adsorbed to an aluminum adjuvant. The vaccine elicited a robust immune response against the two toxins in the rabbits without any adverse events or toxicity. No signs of autoimmune pathology were detected in the rabbits' brains, hearts, and kidneys via immunohistochemistry, and serum antibodies did not cross-react with cardiac or neuronal tissue proteins associated with rheumatic heart disease or Sydenham chorea (SC). This study further confirms that VaxiStrep does not elicit autoantibodies and is safe to be tested in a first-in-human trial.

Improving prioritization processes for clinical practice guidelines: new methods and an evaluation from the National Heart Foundation of Australia.

BACKGROUND: Releasing timely and relevant clinical guidelines is challenging for organizations globally. Priority-setting is crucial, as guideline development is resource-intensive. Our aim, as a national organization responsible for developing cardiovascular clinical guidelines, was to develop a method for generating and prioritizing topics for future clinical guideline development in areas where guidance was most needed. METHODS: Several novel processes were developed, adopted and evaluated, including (1) initial public consultation for health professionals and the general public to generate topics; (2) thematic and qualitative analysis, according to the International Classification of Diseases (ICD-11), to aggregate topics; (3) adapting a criteria-based matrix tool to prioritize topics; (4) achieving consensus through a modified-nominal group technique and voting on priorities; and (5) process evaluation via survey of end-users. The latter comprised the organization's Expert Committee of 12 members with expertise across cardiology and public health, including two citizen representatives. RESULTS: Topics (n = 405; reduced to n = 278 when duplicates removed) were identified from public consultation responses (n = 107 respondents). Thematic analysis synthesized 127 topics that were then categorized into 37 themes using ICD-11 codes. Exclusion criteria were applied (n = 32 themes omitted), resulting in five short-listed topics: (1) congenital heart disease, (2) valvular heart disease, (3) hypercholesterolaemia, (4) hypertension and (5) ischaemic heart diseases and diseases of the coronary artery. The Expert Committee applied the prioritization matrix to all five short-listed topics during a consensus meeting and voted to prioritize topics. Unanimous consensus was reached for the topic voted the highest priority: ischaemic heart disease and diseases of the coronary arteries, resulting in the decision to update the organization's 2016 clinical guidelines for acute coronary syndromes. Evaluation indicated that initial public consultation was highly valued by the Expert Committee, and the matrix tool was easy to use and improved transparency in priority-setting. CONCLUSION: Developing a multistage, systematic process, incorporating public consultation and an international classification system led to improved transparency in our clinical guideline priority-setting processes and that topics chosen would have the greatest impact on health outcomes. These methods are potentially applicable to other national and international organizations responsible for developing clinical guidelines.

A multiplexed in vivo approach to identify driver genes in small cell lung cancer.

Small cell lung cancer (SCLC) is a lethal form of lung cancer. Here, we develop a quantitative multiplexed approach on the basis of lentiviral barcoding with somatic CRISPR-Cas9-mediated genome editing to functionally investigate candidate regulators of tumor initiation and growth in genetically engineered mouse models of SCLC. We found that naphthalene pre-treatment enhances lentiviral vector-mediated SCLC initiation, enabling high multiplicity of tumor clones for analysis through high-throughput sequencing methods. Candidate drivers of SCLC identified from a meta-analysis across multiple human SCLC genomic datasets were tested using this approach, which defines both positive and detrimental impacts of inactivating 40 genes across candidate pathways on SCLC development. This analysis and subsequent validation in human SCLC cells establish TSC1 in the PI3K-AKT-mTOR pathway as a robust tumor suppressor in SCLC. This approach should illuminate drivers of SCLC, facilitate the development of precision therapies for defined SCLC genotypes, and identify therapeutic targets.

Spatial epitope barcoding reveals clonal tumor patch behaviors.

Intratumoral heterogeneity is a seminal feature of human tumors contributing to tumor progression and response to treatment. Current technologies are still largely unsuitable to accurately track phenotypes and clonal evolution within tumors, especially in response to genetic manipulations. Here, we developed epitopes for imaging using combinatorial tagging (EpicTags), which we coupled to multiplexed ion beam imaging (EpicMIBI) for in situ tracking of barcodes within tissue microenvironments. Using EpicMIBI, we dissected the spatial component of cell lineages and phenotypes in xenograft models of small cell lung cancer. We observed emergent properties from mixed clones leading to the preferential expansion of clonal patches for both neuroendocrine and non-neuroendocrine cancer cell states in these models. In a tumor model harboring a fraction of PTEN-deficient cancer cells, we observed a non-autonomous increase of clonal patch size in PTEN wild-type cancer cells. EpicMIBI facilitates in situ interrogation of cell-intrinsic and cell-extrinsic processes involved in intratumoral heterogeneity.

Mapping the network biology of metabolic response to stress in posttraumatic stress disorder and obesity.

The co-occurrence of stress-induced posttraumatic stress disorder (PTSD) and obesity is common, particularly among military personnel but the link between these conditions is unclear. Individuals with comorbid PTSD and obesity manifest other physical and psychological problems, which significantly diminish their quality of life. Current understanding of the pathways connecting stress to PTSD and obesity is focused largely on behavioral mediators alone with little consideration of the biological regulatory mechanisms that underlie their co-occurrence. In this work, we leverage prior knowledge to systematically highlight such bio-behavioral mechanisms and inform on the design of confirmatory pilot studies. We use natural language processing (NLP) to extract documented regulatory interactions involved in the metabolic response to stress and its impact on obesity and PTSD from over 8 million peer-reviewed papers. The resulting network describes the propagation of stress to PTSD and obesity through 34 metabolic mediators using 302 documented regulatory interactions supported by over 10,000 citations. Stress jointly affected both conditions through 21 distinct pathways involving only two intermediate metabolic mediators out of a total of 76 available paths through this network. Moreover, oxytocin (OXT), Neuropeptide-Y (NPY), and cortisol supported an almost direct propagation of stress to PTSD and obesity with different net effects. Although stress upregulated both NPY and cortisol, the downstream effects of both markers are reported to relieve PTSD severity but exacerbate obesity. The stress-mediated release of oxytocin, however, was found to concurrently downregulate the severity of both conditions. These findings highlight how a network-informed approach that leverages prior knowledge might be used effectively in identifying key mediators like OXT though experimental verification of signal transmission dynamics through each path will be needed to determine the actual likelihood and extent of each marker's participation.

A conserved YAP/Notch/REST network controls the neuroendocrine cell fate in the lungs.

The Notch pathway is a conserved cell-cell communication pathway that controls cell fate decisions. Here we sought to determine how Notch pathway activation inhibits the neuroendocrine cell fate in the lungs, an archetypal process for cell fate decisions orchestrated by Notch signaling that has remained poorly understood at the molecular level. Using intratumoral heterogeneity in small-cell lung cancer as a tractable model system, we uncovered a role for the transcriptional regulators REST and YAP as promoters of the neuroendocrine to non-neuroendocrine transition. We further identified the specific neuroendocrine gene programs repressed by REST downstream of Notch in this process. Importantly, we validated the importance of REST and YAP in neuroendocrine to non-neuroendocrine cell fate switches in both developmental and tissue repair processes in the lungs. Altogether, these experiments identify conserved roles for REST and YAP in Notch-driven inhibition of the neuroendocrine cell fate in embryonic lungs, adult lungs, and lung cancer.

Surgical and Functional Outcomes of Bladder Neck Incision for Primary Vesico-Urethral Anastomosis Stricture after Robot-assisted Radical Prostatectomy are Influenced by the Presence of Pre- or Postoperative Radiotherapy.

OBJECTIVE: To report the intermediate- to long-term outcomes of bladder neck incision (BNI) for vesico-urethral anastomosis stricture (VUAS) after robot-assisted radical prostatectomy (RARP) and the influence of pre- or post-RARP radiotherapy on these outcomes. METHODS: A retrospective cohort study was performed with patients who underwent BNI for VUAS after RARP in a high-volume prostatectomy centre between 2006 and July 2021. Data was collected from patient charts. The cohort was divided into 4 groups: VUAS after (1) RARP-only, (2) RARP, but before salvage radiotherapy (SRT) (VUAS pre-SRT), (3) RARP and after SRT (VUAS post-SRT), and (4) primary radiotherapy and salvage RARP (SRARP). The VUAS recurrence rates, the ability to perform functional transurethral micturition and the post-BNI urinary continence rates were reported. RESULTS: BNI was performed in 90 patients. The median time between first BNI and last follow-up was 32 months (interquartile range 10-58, range 0-171). The majority of VUAS occurred within 6 months after (S)RARP. In those who underwent BNI, recurrent VUAS was reported in 12%, 57%, 29%, and 50% of patients after RARP-only, VUAS pre-SRT, VUAS post-SRT, and SRARP, respectively. Ultimately, transurethral micturition was possible in 94%, 93%, 71%, and 80%, respectively. Severe urinary-incontinence rates (>1 pads/d) were 6%, 16%, 10%, and 29% for RARP-only, VUAS pre-SRT, VUAS post-SRT, and SRARP patients, respectively. CONCLUSION: Primary radiotherapy before RARP and SRT after RARP significantly influenced the success rates of BNI. Those who underwent BNI after SRARP had worse outcomes than patients who underwent RARP only.

Surgical Outcomes After Treatment of Urethral Complications Following Metoidioplasty in Transgender Men.

BACKGROUND: Several treatment options for urethral complications following metoidioplasty in transmen are described in the literature, yet little is known with regard to the surgical outcomes. AIM: The aim of this study was to analyze the surgical outcomes after treatment of urethral strictures and urethral fistulas following metoidioplasty. METHODS: A multicenter retrospective cohort study was conducted with transmen treated for strictures and fistulas after metoidioplasty in 3 tertiary referral centers. OUTCOMES: The primary outcome was the recurrence-free rate after surgical treatment of urethral strictures and urethral fistulas over a time period of 3 years postoperatively. RESULTS: Of 96 transmen included in this study with a urethral complication, 44 (46%) experienced a urethral fistula, 31 (32%) a urethral stricture, and 21 (22%) both complications simultaneously. The recurrence-free rate for urethral strictures following endoscopic management (ie, urethral dilation or direct visual internal urethrotomy) was 61% after 1, 50% after 2, and 43% after 3 years, compared to 82% following open treatment options after 1, 2, and 3 years (P = .002). Open treatment options were Heineke-Mikulicz procedure (7/9, 78% success), excision and primary anastomosis (3/3, 100%), 2-stage without graft (9/9, 100%), pedicled flap urethroplasty (1/1, 100%), and buccal mucosa graft urethroplasty (2/4 [50%] single-stage, 1/1 [100%] 2-stage). The recurrence-free rate for small urethral fistulas located at the pendulous urethra was 79% after 1, and 72% after 2 and 3 years, compared to 45% after 1, and 41% after 2 and 3 years for large fistulas, generally located at the urethral anastomoses of the fixed urethra. Treatment options for urethral fistulas were fistulectomy (26/48, 54%), fistulectomy & (redo) colpectomy (7/11, 64%), buccal mucosa graft urethroplasty (1/1, 100%), and retubularization of the urethral plate (3/4, 75%). A colpectomy before or during reoperation of a urethral fistula at the proximal urethral anastomosis showed higher success rates compared to without a colpectomy (7/11 [64%] vs 2/13 [15%] respectively, P = .03). CLINICAL IMPLICATIONS: This study provides insight in the treatment possibilities and corresponding outcomes of urethral complications following metoidioplasty in transmen. STRENGTHS & LIMITATIONS: Strengths were the relatively large sample size and the overview of multiple treatment options available. Limitations were the heterogeneity of the cohort, underexposure of some surgical modalities, and absence of patient-reported outcomes. CONCLUSION: Open surgical techniques show better long-term outcomes in the management of urethral strictures compared to endoscopic options, and a colpectomy is beneficial before or during urethral fistula repair at the proximal urethral anastomosis. de Rooij FPW, Falcone M, Waterschoot M, et al. Surgical Outcomes After Treatment of Urethral Complications Following Metoidioplasty in Transgender Men. J Sex Med 2022;19:377-384.

Anti-GD2 synergizes with CD47 blockade to mediate tumor eradication.

The disialoganglioside GD2 is overexpressed on several solid tumors, and monoclonal antibodies targeting GD2 have substantially improved outcomes for children with high-risk neuroblastoma. However, approximately 40% of patients with neuroblastoma still relapse, and anti-GD2 has not mediated significant clinical activity in any other GD2+ malignancy. Macrophages are important mediators of anti-tumor immunity, but tumors resist macrophage phagocytosis through expression of the checkpoint molecule CD47, a so-called 'Don't eat me' signal. In this study, we establish potent synergy for the combination of anti-GD2 and anti-CD47 in syngeneic and xenograft mouse models of neuroblastoma, where the combination eradicates tumors, as well as osteosarcoma and small-cell lung cancer, where the combination significantly reduces tumor burden and extends survival. This synergy is driven by two GD2-specific factors that reorient the balance of macrophage activity. Ligation of GD2 on tumor cells (a) causes upregulation of surface calreticulin, a pro-phagocytic 'Eat me' signal that primes cells for removal and (b) interrupts the interaction of GD2 with its newly identified ligand, the inhibitory immunoreceptor Siglec-7. This work credentials the combination of anti-GD2 and anti-CD47 for clinical translation and suggests that CD47 blockade will be most efficacious in combination with monoclonal antibodies that alter additional pro- and anti-phagocytic signals within the tumor microenvironment.

Incidence of testicular cancer in trans women using gender-affirming hormonal treatment: a nationwide cohort study.

OBJECTIVE: To assess the incidence of testicular cancer in trans women (male sex assigned at birth, female gender identity) using gender-affirming hormonal treatment. PATIENTS AND METHODS: Data of trans women starting hormonal treatment at our gender identity clinic between 1972 and 2017 were linked to the national pathology database to obtain testicular cancer diagnoses. The standardised incidence ratio (SIR) was calculated using the number of observed testicular cancer cases in our cohort and the number of expected cases based on age-specific Dutch incidence rates. Subgroup analyses were performed in testicular tissues sent for histopathological analysis at the time of bilateral orchidectomy, and when follow-up exceeded 5 years. RESULTS: The cohort consisted of 3026 trans women with a median follow-up time of 2.3 interquartile range (IQR) (1.6-3.7) years. Two testicular cancer cases were identified whilst 2.4 cases were expected (SIR 0.8, 95% confidence interval 0.1-2.8). In addition, one testicular cancer case was encountered in an orchidectomy specimen (0.1%). In the 523 trans women with a follow-up time of >5 years (median [IQR] 8.9 [6.4-13.9] years), no testicular cancer was observed. CONCLUSION: Testicular cancer risk in trans women is similar to the risk in cis men. The testicular cancer cases occurred within the first 5 years after commencing hormonal treatment, and the percentage of cases encountered at the time of bilateral orchidectomy was low. As no testicular cancer was observed in trans women with a long follow-up period, long-term hormonal treatment does not seem to increase testicular cancer risk.

Surgical outcomes and proposal for a treatment algorithm for urethral strictures in transgender men.

OBJECTIVES: To assess our results of surgical treatment for urethral strictures in transgender men, and to provide a surgical treatment algorithm. PATIENTS AND METHODS: A single centre, retrospective cohort study was conducted of transgender men who underwent surgical correction of their urethral stricture(s) between January 2013 and March 2020. The medical charts of 72 transgender men with 147 urethral strictures were reviewed. The primary outcomes were the success and recurrence rates after surgical treatment for urethral strictures. RESULTS: The median (interquartile range [IQR]) follow-up was 61 (25-202) months. At last follow-up, 50/72 (69%) were able to void while standing (after one [60%], two [20%], three [6%], four [8%], five [4%], or seven [2%] procedures), 10/72 (14%) await further treatment, two of the 72 (3%) sat to void despite good urodynamic function, and 10/72 (14%) had a definitive urethrostomy. Of 104 surgical treatments included in separate success rate analysis, 65 (63%) were successful (43/75 [57%] after phalloplasty, 22/29 [76%] after metoidioplasty). The highest success rates in short urethral strictures were seen after a Heineke-Mikulicz procedure (six of seven cases), and in longer or more complicated urethral strictures after two-stage with graft (four of six), two-stage without graft (10/12), pedicled flap (11/15, 73%), and single-stage graft (seven of seven) urethroplasties. Grafts used were buccal mucosa or full-thickness skin grafts. Success rates improved over time, with success rates of 38% and 36% in 2013 and 2014, to 71% and 73% in 2018 and 2019, respectively. We concluded with a surgical treatment algorithm based on previous literature, stricture characteristics, and our surgical outcomes. CONCLUSION: The highest success rates were seen after a Heineke-Mikulicz procedure in short urethral strictures; and after graft, pedicled flap, or two-stage urethroplasties in longer or more complicated urethral strictures. Finally, most of the transgender men were able to void while standing, although in some multiple surgical procedures were necessary to accomplish this.

Deep learning-based classification of kidney transplant pathology: a retrospective, multicentre, proof-of-concept study.

BACKGROUND: Histopathological assessment of transplant biopsies is currently the standard method to diagnose allograft rejection and can help guide patient management, but it is one of the most challenging areas of pathology, requiring considerable expertise, time, and effort. We aimed to analyse the utility of deep learning to preclassify histology of kidney allograft biopsies into three main broad categories (ie, normal, rejection, and other diseases) as a potential biopsy triage system focusing on transplant rejection. METHODS: We performed a retrospective, multicentre, proof-of-concept study using 5844 digital whole slide images of kidney allograft biopsies from 1948 patients. Kidney allograft biopsy samples were identified by a database search in the Departments of Pathology of the Amsterdam UMC, Amsterdam, Netherlands (1130 patients) and the University Medical Center Utrecht, Utrecht, Netherlands (717 patients). 101 consecutive kidney transplant biopsies were identified in the archive of the Institute of Pathology, RWTH Aachen University Hospital, Aachen, Germany. Convolutional neural networks (CNNs) were trained to classify allograft biopsies as normal, rejection, or other diseases. Three times cross-validation (1847 patients) and deployment on an external real-world cohort (101 patients) were used for validation. Area under the receiver operating characteristic curve (AUROC) was used as the main performance metric (the primary endpoint to assess CNN performance). FINDINGS: Serial CNNs, first classifying kidney allograft biopsies as normal (AUROC 0·87 [ten times bootstrapped CI 0·85-0·88]) and disease (0·87 [0·86-0·88]), followed by a second CNN classifying biopsies classified as disease into rejection (0·75 [0·73-0·76]) and other diseases (0·75 [0·72-0·77]), showed similar AUROC in cross-validation and deployment on independent real-world data (first CNN normal AUROC 0·83 [0·80-0·85], disease 0·83 [0·73-0·91]; second CNN rejection 0·61 [0·51-0·70], other diseases 0·61 [0·50-0·74]). A single CNN classifying biopsies as normal, rejection, or other diseases showed similar performance in cross-validation (normal AUROC 0·80 [0·73-0·84], rejection 0·76 [0·66-0·80], other diseases 0·50 [0·36-0·57]) and generalised well for normal and rejection classes in the real-world data. Visualisation techniques highlighted rejection-relevant areas of biopsies in the tubulointerstitium. INTERPRETATION: This study showed that deep learning-based classification of transplant biopsies could support pathological diagnostics of kidney allograft rejection. FUNDING: European Research Council; German Research Foundation; German Federal Ministries of Education and Research, Health, and Economic Affairs and Energy; Dutch Kidney Foundation; Human(e) AI Research Priority Area of the University of Amsterdam; and Max-Eder Programme of German Cancer Aid.

Phase 1b dose-escalation, safety, and pharmacokinetic study of IC14, a monoclonal antibody against CD14, for the treatment of amyotrophic lateral sclerosis.

BACKGROUND: The primary objective was to demonstrate the safety and tolerability of monoclonal antibody against CD14 (IC14) (atibuclimab) in amyotrophic lateral sclerosis patients. The secondary objectives were pharmacokinetics, pharmacodynamics, and preliminary effects on disease status and biomarkers. METHODS: In this open-label, dose-escalation trial, IC14 was administered at 2 mg/kg intravenous (IV) followed by 1 mg/kg/d IV × 3 (n = 3) and in subsequent patients at 4 mg/kg IV followed by 2 mg/kg/d IV × 3 (n = 7) (NCT03487263). Disease status was measured using the Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, forced vital capacity, sniff nasal pressure, Edinburgh Cognitive and Behavioural ALS Screen, and Revised ALS-Specific Quality-of-Life Score. Disease biomarkers included cerebrospinal fluid and serum levels of neurofilament light chain (NfL) and urinary p75 neurotrophin receptor. RESULTS: IC14 was safe and well tolerated. No antidrug antibodies were detected. The drug target saturation of monocyte CD14 receptors was rapid and sustained through day 8. There was no significant change in Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, forced vital capacity, sniff nasal pressure, or Revised ALS-Specific Quality-of-Life Score following a single cycle of treatment. Cerebrospinal fluid NfL levels decreased in 6 of 9 patients sampled with declines of 15% to 40% between baseline (not significant [ns]) and day 8 in 3 patients. Serum NfL modestly decreased in 5 of 10 patients (ns) at day 8 and was sustained in 4 (4%-37%, ns) over 33 days of follow up. CONCLUSION: IC14 quickly and durably saturated its target in all patients. This study demonstrated safety and tolerability in patients with amyotrophic lateral sclerosis. Even though only a single cycle of treatment was given, there were promising beneficial trends in the neurofilament light chain, a disease biomarker. The emerging understanding of the role of systemic inflammation in neurodegenerative diseases, and the potential for IC14 to serve as a safe, potent, and broad-spectrum inhibitor of immune dysregulation merits further clinical study. CLINICAL TRIAL REGISTRATION: NCT03487263.

NSD2 dimethylation at H3K36 promotes lung adenocarcinoma pathogenesis.

The etiological role of NSD2 enzymatic activity in solid tumors is unclear. Here we show that NSD2, via H3K36me2 catalysis, cooperates with oncogenic KRAS signaling to drive lung adenocarcinoma (LUAD) pathogenesis. In vivo expression of NSD2E1099K, a hyperactive variant detected in individuals with LUAD, rapidly accelerates malignant tumor progression while decreasing survival in KRAS-driven LUAD mouse models. Pathologic H3K36me2 generation by NSD2 amplifies transcriptional output of KRAS and several complementary oncogenic gene expression programs. We establish a versatile in vivo CRISPRi-based system to test gene functions in LUAD and find that NSD2 loss strongly attenuates tumor progression. NSD2 knockdown also blocks neoplastic growth of PDXs (patient-dervived xenografts) from primary LUAD. Finally, a treatment regimen combining NSD2 depletion with MEK1/2 inhibition causes nearly complete regression of LUAD tumors. Our work identifies NSD2 as a bona fide LUAD therapeutic target and suggests a pivotal epigenetic role of the NSD2-H3K36me2 axis in sustaining oncogenic signaling.

How Sensitive Is the Neophallus? Postphalloplasty Experienced and Objective Sensitivity in Transmasculine Persons.

INTRODUCTION: Tactile and erogenous sensitivity of the neophallus after phalloplasty is assumed to affect the sexual well-being of transmasculine persons and, ultimately, their quality of life. The experienced and objective sensation of the neophallus and their association are largely unknown. AIM: This study evaluated experienced tactile and erotic sensation of the neophallus in transmasculine persons and investigated how this was related to objective tactile sensitivity. METHODS: Between August 2017 and January 2020, 59 transmasculine persons who underwent phalloplasty were recruited to participate in a prospective follow-up study. Tactile sensitivity of the neophallus and donor-site was measured (Semmes-Weinstein Monofilament test) and compared, and participants were asked to fill out a questionnaire about experienced sensation of the neophallus and sexual wellbeing. MAIN OUTCOME MEASURES: Experienced and objective sensation of the neophallus were measured by using a questionnaire and Semmes-Weinstein Monofilament scores. RESULTS: Neophallic tactile sensitivity was significantly reduced compared to the donor-site (n = 44), with the proximal part being more sensitive than the distal part (median follow-up of 1.8 years, range 1.0-7.2)). Sensitivity of the neophallus was not significantly associated with the surgical flap used, yet increased significantly with follow-up time. The questionnaire was completed by 26 participants of which 24 (92.3%) experienced (some degree of) tactile sensitivity in their neophallus. Erogenous sensation was experienced by 23 (88.5%). Experienced and objectified tactile sensitivity were not significantly correlated (Spearmans's rho = 0.23, P = .26). Answers to open-ended questions showed that results often do not match expectations. CONCLUSION: Tactile sensation of the neophallus was reduced in most transmasculine persons and improved slowly over time. A significant association between subjective and objective measures could not be detected. Although experienced sensitivity varied between individuals, the vast majority reported to have tactile and erotic sensitivity in the neophallus.Transmasculine persons should be informed that sensitivity of the neophallus will likely be reduced. Elfering L, van de Grift TC, Al-Tamimi M, et al. How Sensitive Is the Neophallus? Postphalloplasty Experienced and Objective Sensitivity in Transmasculine Persons. Sex Med 2021;9:100413.

Surgical outcomes of testicular prostheses implantation in transgender men with a history of prosthesis extrusion or infection.

Background: Testicular prostheses implantation may be used for neoscrotal augmentation in transgender men. In current literature, explantation rates range from 0.6% to 30% and most are a result of infection or extrusion. Information on the surgical path of individuals after prosthesis explantation is scarce. Aim: To assess the frequency and success rate of testicular prosthesis implantation after previous explantation due to infection or extrusion. Methods: All transgender men who underwent testicular prosthesis explantation between January 1991 and December 2018 were retrospectively identified from a departmental database. A retrospective chart study was conducted, recording demographics, surgical and prosthesis characteristics, reoperations, and outcomes. Results: A total of 41 transgender men were included who underwent testicular prosthesis explantation in the study time period. Of these, 28 (68%) opted for new prosthesis implantation. Most explanted prosthesis had a volume ≥30cc and were replaced with an equally sized one. The postoperative course was uneventful in 19 out of 28 (68%) individuals. Explantation of one or both prostheses occurred in 7 out of 28 (25%) individuals, because of infection (n = 3, 11%) or extrusion (n = 4, 14%). Patients that experienced complications had more often a history of smoking (p = 0.049). The explantation rate was lower if a smaller or lighter prosthesis was reimplanted (p = 0.020). Discussion: Most patients opt for testicular prosthesis implantation after previous explantation due to extrusion or infection. Explantation rates are higher than after the primary implantation procedure. Results of current study can be used to inform individuals on postoperative outcomes.