Illegal synthetic dyes in spices: a Singapore case study.

Some synthetic dyes are fraudulently added into spices to appeal visually to consumers. Food regulations in several countries, including the United States, Australia, Japan and the European Union, strictly prohibit the use of unauthorised synthetic dyes in food. Nevertheless, illegal practices persist, where spices contaminated with potentially carcinogenic dyes have been documented, posing potential health risks to consumers. In the present study, 14 synthetic dyes were investigated through liquid chromatography/tandem mass spectrometry in 252 commercially available spices in the Singapore market. In 18 out of these (7.1%) at least 1 illegal dye was detected at concentrations ranging from 0.010 to 114 mg/kg. Besides potential health risks, presence of these adulterants also reflects the economic motivations behind their fraudulent use. Findings in the present study further emphasise the need for increased public awareness, stricter enforcement, and continuous monitoring of illegal synthetic dyes in spices to ensure Singapore's food safety.

VSIG4 interaction with heparan sulfates inhibits VSIG4-complement binding.

V-set and immunoglobulin domain-containing 4 (VSIG4) is a complement receptor of the immunoglobulin superfamily that is specifically expressed on tissue resident macrophages, and its many reported functions and binding partners suggest a complex role in immune function. VSIG4 is reported to have a role in immune surveillance as well as in modulating diverse disease phenotypes such as infections, autoimmune conditions, and cancer. However, the mechanism(s) governing VSIG4's complex, context-dependent role in immune regulation remains elusive. Here, we identify cell surface and soluble glycosaminoglycans, specifically heparan sulfates, as novel binding partners of VSIG4. We demonstrate that genetic deletion of heparan sulfate synthesis enzymes or cleavage of cell-surface heparan sulfates reduced VSIG4 binding to the cell surface. Furthermore, binding studies demonstrate that VSIG4 interacts directly with heparan sulfates, with a preference for highly sulfated moieties and longer glycosaminoglycan chains. To assess the impact on VSIG4 biology, we show that heparan sulfates compete with known VSIG4 binding partners C3b and iC3b. Furthermore, mutagenesis studies indicate that this competition occurs through overlapping binding epitopes for heparan sulfates and complement on VSIG4. Together these data suggest a novel role for heparan sulfates in VSIG4-dependent immune modulation.

Validation of user-friendly models predicting extracapsular extension in prostate cancer patients.

Objective: There are many models to predict extracapsular extension (ECE) in patients with prostate cancer. We aimed to externally validate several models in a Japanese cohort. Methods: We included patients treated with robotic-assisted radical prostatectomy for prostate cancer. The risk of ECE was calculated for each patient in several models (prostate side-specific and non-side-specific). Model performance was assessed by calculating the receiver operating curve and the area under the curve (AUC), calibration plots, and decision curve analyses. Results: We identified ECE in 117 (32.9%) of the 356 prostate lobes included. Patients with ECE had a statistically significant higher prostate-specific antigen level, percentage of positive digital rectal examination, percentage of hypoechoic nodes, percentage of magnetic resonance imaging nodes or ECE suggestion, percentage of biopsy positive cores, International Society of Urological Pathology grade group, and percentage of core involvement. Among the side-specific models, the Soeterik, Patel, Sayyid, Martini, and Steuber models presented AUC of 0.81, 0.78, 0.77, 0.75, and 0.73, respectively. Among the non-side-specific models, the memorial Sloan Kettering Cancer Center web calculator, the Roach formula, the Partin tables of 2016, 2013, and 2007 presented AUC of 0.74, 0.72, 0.64, 0.61, and 0.60, respectively. However, the 95% confidence interval for most of these models overlapped. The side-specific models presented adequate calibration. In the decision curve analyses, most models showed net benefit, but it overlapped among them. Conclusion: Models predicting ECE were externally validated in Japanese men. The side-specific models predicted better than the non-side-specific models. The Soeterik and Patel models were the most accurate performing models.

Novel nomogram to predict biochemical recurrence-free survival after radical prostatectomy.

PURPOSE: Conditional survival represents the probability of subsequent survival given that patients have already survived a certain length of time. Several models predict biochemical recurrence (BCR) after radical prostatectomy. However, none of them include postoperative prostate-specific antigen (PSA). We aimed to analyze BCR-free survival evolution over time and develop a nomogram incorporating the postoperative PSA value to predict BCR-free survival. MATERIAL AND METHODS: We included patients treated with robot-assisted radical prostatectomy (RARP) for prostate cancer between 2009 and 2021 and calculated conditional survival. Cox proportional hazard regression analysis was used to assess the predictive variables of BCR. We developed a nomogram predicting BCR-free survival three and five years after RARP. We used c-index and decision curve analyses to compare the nomogram with the Cancer of the Prostate Risk Assessment post-Surgical (CAPRA-S) score. RESULTS: We included 718 patients. The overall 3- and 5-year BCR-free survival rates were 85.1% and 75.7%, respectively. The 5-year BCR-free survival rates increased to 78.9%, 82.9%, 85.2%, and 84.7% for patients surviving 1, 2, 3, and 4 years without BCR, respectively. We developed a nomogram including the pathological Gleason score and T stage, positive surgical margin, PSA ≥ 0.05 ng/mL at one year, and lymph node involvement to predict BCR at 3 and 5 years postoperatively. Our nomogram presented a higher c-index (0.89) than the CAPRA-S score (0.78; p = 0.001) and a positive net benefit at 3 and 5 years postoperatively in the decision curve analyses. CONCLUSION: The 5-year conditional BCR-free survival increased with survival without BCR. The developed nomogram significantly improved the accuracy in predicting BCR-free survival after RARP.

Correlation between extended pelvic lymph node dissection and urinary incontinence at early phase after robot-assisted radical prostatectomy.

OBJECTIVES: To investigate the impact of extended pelvic lymph node dissection (ePLND) on urinary incontinence (UI) at early post-surgery robot-assisted radical prostatectomy (RARP). METHODS: Patients who underwent RARP without cavernous nerve sparing were included between 2014 and 2019. Patient data were obtained prospectively. The associations between ePLND and postoperative urinary continence were defined as a maximum of one daily pad use. International prostate symptom score (IPSS) was examined. Expression of synaptophysin and tyrosine hydroxylase (TH) in perilymph node adipose tissue (PLA) was evaluated by immunohistochemistry. RESULTS: In total, 186 and 163 patients underwent RARP with and without ePLND. Urinary continence rate at 1 month postoperatively among patients with ePLND was lower than those without ePLND (24.1% vs. 35.1%, p < 0.05), however, not significantly different at 3, 6, and 12 months after RARP (57.4 vs. 62.6%, 73.1 vs. 74.2%, and 83.0 vs. 81.2%, respectively). Total and voiding plus postvoiding IPSS scores at 1 month were higher in patients with ePLND than in those without ePLND (14.5 ± 0.5 vs. 13.6 ± 0.6, 7.0 ± 0.3 vs. 6.2 ± 0.4, respectively, p < 0.05). In univariate and multivariate analyses, larger prostate volume and ePLND were factors associated with an increased UI rate. Among patients who underwent ePLND, synaptophysin and TH-positive nerve fibers were detected in PLA. CONCLUSIONS: Detection of synaptophysin and TH-immunopositive nerves suggested denervation of sympathetic and peripheral nerves caused by ePLND might be associated with a higher UI rate and poor urinary symptoms at an early stage after RARP.

Psoas Muscle Volume Is a Predictive Marker of Fatigue and Anorexia in Prostate Cancer Patients Treated with Enzalutamide.

Introduction: Enzalutamide is approved for the treatment of patients with metastatic castration-resistant prostate cancer. Adverse effects (e.g., fatigue and anorexia) are often observed and cause difficulty with continuous therapy; however, no clinical data describing which patients are more likely to suffer adverse effects were observed. Therefore, this study hypothesized that body composition, comprising body fat distribution and psoas muscle volume, may affect the occurrence of subjective symptoms (e.g., fatigue and anorexia) in prostate cancer patients treated with enzalutamide. Methods: Adverse effects, especially fatigue, anorexia, insomnia, and pain, were retrospectively evaluated by CTCAE v4.0 criteria. Sixty-seven prostate cancer patients treated with enzalutamide were enrolled, and body fat, visceral fat percentage, and psoas muscle ratio (psoas muscle, in cubic centimeter/height, in meters) were calculated using computed tomography images evaluated before enzalutamide, with SYNAPSE VINCENT software. Univariate analysis was performed to identify the factors associated with adverse effects. Results: Univariate analysis showed that high psoas muscle ratio was significantly associated with fatigue (grade ≥ 2; odds ratio, 3.875; 95% confidence interval, 1.016-17.134; P = 0.047), but inversely related to anorexia (grade ≥ 2; odds ratio, 0.093; 95% confidence interval, 0.011-0.784; P = 0.029). Conclusions: Psoas muscle ratio is a predictive marker of fatigue and anorexia in patients treated with enzalutamide.

CD22-targeted CD28 bispecific antibody enhances antitumor efficacy of odronextamab in refractory diffuse large B cell lymphoma models.

Although many patients with diffuse large B cell lymphoma (DLBCL) may achieve a complete response to frontline chemoimmunotherapy, patients with relapsed/refractory disease typically have poor outcomes. Odronextamab, a CD20xCD3 bispecific antibody that provides "signal 1" through the activation of the T cell receptor/CD3 complex, has exhibited early, promising activity for patients with highly refractory DLBCL in phase 1 trials. However, not all patients achieve complete responses, and many relapse, thus representing a high unmet medical need. Here, we investigated whether adding a costimulatory "signal 2" by engaging CD28 receptors on T cells could augment odronextamab activity. We demonstrate that REGN5837, a bispecific antibody that cross-links CD22-expressing tumor cells with CD28-expressing T cells, enhances odronextamab by potentiating T cell activation and cytolytic function. In preclinical DLBCL studies using human immune system-reconstituted animals, REGN5837 promotes the antitumor activity of odronextamab and induces intratumoral expansion of reprogrammable T cells while skewing away from a dysfunctional state. Although REGN5837 monotherapy shows limited activity and no toxicity in primate studies, it augments T cell activation when dosed in combination with odronextamab. In addition, analysis of non-Hodgkin lymphoma clinical samples reveals an increase in CD28+CD8+ T cells after odronextamab treatment, demonstrating the presence of a population that could potentially be targeted by REGN5837. Collectively, our data demonstrate that REGN5837 can markedly enhance the antitumor activity of odronextamab in preclinical NHL models, and the combination of these two bispecific antibodies may provide a chemotherapy-free approach for the treatment of DLBCL.

Synthesis of (+)-ribostamycin by catalytic, enantioselective hydroamination of benzene.

Aminoglycosides (AGs) represent a large group of pseudoglycoside natural products, in which several different sugar moieties are harnessed to an aminocyclitol core. AGs constitute a major class of antibiotics that target the prokaryotic ribosome of many problematic pathogens. Hundreds of AGs have been isolated to date, with 1,3-diaminocyclohexanetriol, known as 2-deoxystreptamine (2-DOS), being the most abundant aglycon core. However, owning to their diverse and complex architecture, all AG-based drugs are either natural substances or analogues prepared by late-stage modifications. Synthetic approaches to AGs are rare and lengthy; most studies involve semi-synthetic reunion of modified fragments. Here we report a bottom-up chemical synthesis of the 2-DOS-based AG antibiotic ribostamycin, which proceeds in ten linear operations from benzene. A key enabling transformation involves a Cu-catalyzed, enantioselective, dearomative hydroamination, which set the stage for the rapid and selective introduction of the remaining 2-DOS heteroatom functionality. This work demonstrates how the combination of a tailored, dearomative logic and strategic use of subsequent olefin functionalizations can provide practical and concise access to the AG class of compounds.

Testosterone level in seminal vesicle fluid is a better indicator of erectile function than serum testosterone in patients with prostate cancer.

OBJECTIVES: Semen comprises prostatic fluid and seminal vesicle fluid, and seminal vesicle fluid contains various factors such as prostaglandin E2 (PGE2), zinc, and testosterone, which play important roles in sperm motility. It is not known whether these factors affect erectile function. In this study, we investigated factors in seminal vesicle fluid that may affect erectile function. METHODS: After receiving institutional review board approval, we collected seminal vesicle fluid samples from 134 Japanese patients with localized prostate cancer who underwent robot-assisted radical prostatectomy. We examined the relationship between the results of the Sexual Health Inventory for Men (SHIM), erection hardness score, an original questionnaire on the presence or absence of sexual desire, and concentrations of several factors in seminal vesicle fluid (testosterone, PGE2, transforming growth factor ß1, and 8-hydroxy-2-deoxyguanosine), as well as the serum testosterone level. RESULTS: Median participant age was 67 (range 51-77) years. Median concentrations were as follows: seminal vesicle testosterone 1.85 (range 0.17-4.32) ng/ml and serum testosterone 4.60 (range 1.75-10.82) ng/ml. When the SHIM score was divided into two groups, seminal vesicle testosterone concentration was significantly increased (p = 0.002) in participants with a SHIM score ≥17, and no significant difference was observed in serum testosterone levels (p = 0.661). Multivariate analysis revealed that seminal vesicle testosterone was significantly correlated with the SHIM score (≥17 vs. <17; odds ratio 2.137, 95% confidence interval 1.148-3.978, p = 0.016). CONCLUSIONS: Testosterone levels in seminal vesicle fluid can reflect erectile function in patients with prostate cancer, suggesting that seminal vesicle testosterone is very important for male erectile function.

Impact of nerve sparing in robot-assisted radical prostatectomy on the risk of positive surgical margin and biochemical recurrence.

OBJECTIVES: Nerve sparing may increase positive surgical margin rate during radical prostatectomy. Our objective was to analyze the positive surgical margin rate and location as well as its impact on biochemical recurrence according to nerve sparing procedure in robot-assisted radical prostatectomy. METHODS: We included 814 patients treated with robot-assisted radical prostatectomy between 2009 and 2021, and evaluated the impact of nerve sparing on positive surgical margin and biochemical recurrence using logistic regression and Cox models. RESULTS: Unilateral nerve sparing and bilateral nerve sparing were performed in 152 (18.6%) cases and 118 (14.5%) cases, respectively. On multivariable analysis, in addition to nerve sparing, bilateral nerve sparing, but not unilateral nerve sparing was associated with an increased risk of positive surgical margin compared with non-nerve sparing. Positive surgical margin at any location increased the risk of biochemical recurrence. During unilateral nerve sparing, positive surgical margin in nerve sparing side, but not in non-nerve sparing side was associated with increased risk of biochemical recurrence on multivariate analysis. CONCLUSIONS: Taken together, surgeons need to notice an increased risk of biochemical recurrence associated with positive surgical margin when performing nerve sparing in robot-assisted radical prostatectomy, and then need to choose the patients suitable for nerve sparing.

Anticancer Effect of Second-line Treatment for Castration-Resistant Prostate Cancer Following First-line Treatment with Androgen Receptor Pathway Inhibitors.

INTRODUCTION: Studies on the effect of androgen receptor pathway inhibitors (ARPI), docetaxel (DTX), and radium-223 (Ra-223) after first-line treatment with ARPI in patients with castration-resistant prostate cancer (CRPC) are scarce. This study compared the efficacy of treatment after ARPI for CRPC. METHODS: Patients with CRPC who received ARPI as first-line treatment and different second-line treatments were retrospectively reviewed. Clinicopathological backgrounds and treatment outcomes, including maximum prostate-specific antigen (PSA) decrease, progression-free survival (PFS), and overall survival (OS), were compared between second-line treatments. RESULTS: In total, 88 patients were enrolled. Forty-one (46.6%), 37 (42.0%), and 10 (11.4%) patients were treated with ARPI, DTX, and Ra-223, respectively. Patients whose PSA levels were not adequately reduced by first-line treatment with ARPI were eventually enrolled in the DTX treatment (P = 0.030). PSA decrease was not significantly different when comparing treatments. PFS in the DTX group was significantly better than in the other two groups (P = 0.023). In multivariate analysis, DTX was an independent prognostic factor for better PFS compared to ARPI (hazard ratio, 95% confidence interval; 0.44, 0.25-0.79, P = 0.006). Subgroup analysis showed a favorable impact of DTX on PFS in patients with Gleason score >8 (interaction P = 0.027) and a PSA decline >50% (interaction P = 0.019) during first-line treatment with ARPI. However, no significant difference in OS was observed between groups of different second-line treatments. CONCLUSIONS: This study suggests that in patients with CRPC, second-line treatment with DTX following progression in patients who received ARPI as first-line treatment is more beneficial compared with second-line treatment with ARPI or Ra-233.

Cerebellar Stroke in a COVID-19 Infected Patient. a Case Report.

BACKGROUND: Recent studies have reported that COVID-19 infected patients with stroke, who were often in the older age group, had a higher incidence of vascular risk factors, and more severe infection related respiratory symptoms. These observations provided little evidence to suggest that COVID-19 infection is a potential causative factor for stroke. This report describes a young patient with a cerebellar stroke secondary to COVID-19 infection. CASE PRESENTATION: A 45-year old male presented at a hospital, reporting a two-day history of headache, vertigo, persistent vomiting, and unsteady gait. Physical examination revealed gaze-evoked nystagmus on extraocular movement testing, left-sided dysmetria and dysdiadochokinesia. He was diagnosed with a left cerebellar stroke. An external ventricular drain was inserted, and sub-occipital craniectomy was performed to manage the effects of elevated intracranial pressure due to the extent of oedema secondary to the infarct. He also underwent screening for the COVID-19 infection, which was positive on SARS-COV-2 polymerase chain reaction testing of his endotracheal aspirate. Blood and cerebrospinal fluid samples were negative. After the surgery, the patient developed atrial fibrillation and had prolonged vomiting symptoms, but these resolved eventually with symptomatic treatment. He was started on aspirin and statin therapy, but anticoagulation was withheld due to bleeding concerns. The external ventricular drain was removed nine days after the surgery. He continued with active rehabilitation. CONCLUSIONS: Young patients with COVID-19 infection may be more susceptible to stroke, even in the absence of risk factors. Standard treatment with aspirin and statins remains essential in the management of COVID-19 related stroke. Anticoagulation for secondary prevention in those with atrial fibrillation should not be routine and has to be carefully evaluated for its benefits compared to the potential harms of increased bleeding associated with COVID-19 infection.

Heterogeneity of non-cystic-fibrosis bronchiectasis in multiethnic Singapore: A prospective cohort study at a tertiary pulmonology centre.

INTRODUCTION: Non-cystic fibrosis bronchiectasis (NCFB) is a highly heterogenous disease. We describe the clinical characteristics of NCFB patients and evaluate the performance of Bronchiectasis Severity Index (BSI) in predicting mortality. METHODS: Patients attending the bronchiectasis clinic between August 2015 and April 2020 with radiologically proven bronchiectasis on computed tomography were recruited. Clinical characteristics, spirometry, radiology, microbiology and clinical course over a median period of 2.4 years is presented. RESULTS: A total of 168 patients were enrolled in this prospective cohort study. They were predominantly women (67.8%), Chinese (87.5%) and never-smokers (76.9%). Median age of diagnosis was 64 years (interquartile range 56-71) and the most common aetiology was "idiopathic" bronchiectasis (44.6%). Thirty-nine percent had normal spirometries. Compared to female patients, there were more smokers among the male patients (53.8% versus 8.5%, P<0.001) and a significantly larger proportion with post-tuberculous bronchiectasis (37.0% vs 15.8%, P=0.002). Fifty-five percent of our cohort had a history of haemoptysis. Lower body mass index, presence of chronic obstructive pulmonary disease, ever-smoker status, modified Reiff score, radiological severity and history of exacerbations were risk factors for mortality. Survival was significantly shorter in patients with severe bronchiectasis (BSI>9) compared to those with mild or moderate disease (BSI<9). The hazard ratio for severe disease (BSI>9) compared to mild disease (BSI 0-4) was 14.8 (confidence interval 1.929-114.235, P=0.01). CONCLUSION: The NCFB cohort in Singapore has unique characteristics with sex differences. Over half the patients had a history of haemoptysis. The BSI score is a useful predictor of mortality in our population.

Total Synthesis and Computational Investigations of Sesquiterpene-Tropolones Ameliorate Stereochemical Inconsistencies and Resolve an Ambiguous Biosynthetic Relationship.

The sesquiterpene-tropolones belong to a distinctive structural class of meroterpene natural products with impressive biological activities, including anticancer, antifungal, antimalarial, and antibacterial. In this article, we describe a concise, modular, and cycloaddition-based approach to a series of sesquiterpene mono- and bistropolones, including (-)-epolone B, (+)-isoepolone B, (±)-dehydroxypycnidione, and (-)-10-epi-pycnidione. Alongside the development of a general strategy to access this unique family of metabolites were computational modeling studies that justified the diastereoselectivity observed during key cycloadditions. Ultimately, these studies prompted stereochemical reassignments of the pycnidione subclass and shed additional light on the biosynthesis of these remarkable natural products.

Mutations in BRCA1 and BRCA2 differentially affect the tumor microenvironment and response to checkpoint blockade immunotherapy.

Immune checkpoint blockade (ICB) has improved outcomes for patients with advanced cancer, but the determinants of response remain poorly understood. Here we report differential effects of mutations in the homologous recombination genes BRCA1 and BRCA2 on response to ICB in mouse and human tumors, and further show that truncating mutations in BRCA2 are associated with superior response compared to those in BRCA1. Mutations in BRCA1 and BRCA2 result in distinct mutational landscapes and differentially modulate the tumor-immune microenvironment, with gene expression programs related to both adaptive and innate immunity enriched in BRCA2-deficient tumors. Single-cell RNA sequencing further revealed distinct T cell, natural killer, macrophage, and dendritic cell populations enriched in BRCA2-deficient tumors. Taken together, our findings reveal the divergent effects of BRCA1 and BRCA2-deficiency on ICB outcome, and have significant implications for elucidating the genetic and microenvironmental determinants of response to immunotherapy.

New mouse model of underactive bladder developed by placement of a metal ring around the bladder neck.

OBJECTIVE: To develop a new mouse model of underactive bladder (UAB) caused by chronic bladder outlet obstruction (BOO). METHODS: BOO was created in 6-week-old male C57BL/6 mice using surgery to loosely place a silver jump ring around the bladder neck of each mouse. Micturition behavior (assessed with a metabolic cage) and cystometry were used to evaluate bladder function at 8 and 16 weeks after BOO. Following completion of the functional studies, the bladders of the mice were excised, weighed, and subjected to histological analysis. RESULTS: Micturition behavior analysis showed that mice subjected to BOO for 16 weeks had a lower frequency of micturition (7.3 ± 1.1 vs 12.5 ± 3.0 times/d, P < .05) and volume per void (106.0 ± 0.1 vs 133.9 ± 3.2 µL, P < .05) than mice subjected to BOO for 8 weeks. Cystometry revealed that mice subjected to BOO for 16 weeks had lower baseline pressure (8.4 ± 0.6 vs 14.0 ± 0.7 cmH2 O, P < .01) and micturition pressure (13.9 ± 1.1 vs 42.8 ± 1.7 cmH2 O, P < .05) than mice subjected to BOO for 8 weeks. BOO caused progressive increases in bladder mass and collagen deposition over time. CONCLUSIONS: We successfully established a novel mouse model of UAB using surgery to place a silver jump ring loosely on the bladder neck. BOO initially induced bladder overactivity but subsequently resulted in UAB due to deterioration of detrusor smooth muscle contractility and progressive deposition of collagen in the bladder wall.

Apoiando a educação em pesquisa dos graduandos de enfermagem / Apoyando la educación para la investigación de los estudiantes de enfermería de pregrado / Sustaining undergraduate nursing students' research education

Resumo Objetivos Descrever a experiência da implementação de um programa de treinamento de assistente de pesquisa voluntário para graduandos canadenses de Enfermagem, objetivando o desenvolvimento de habilidades de comunicação verbal e escrita, métodos de pesquisa e análise de dados, pensamento crítico e resolução de problemas, assim como o planejamento de suas carreiras e o avanço de seus papéis relacionados à pesquisa e às oportunidades administrativas e de liderança. Método Estudo descritivo com relato de experiência sobre o processo de treinamento para um novo papel profissional relativo ao engajamento dos graduandos em 11 oficinas, cada uma com duração de uma hora e o processo de apoiá-los para assumir papéis profissionais e de liderança. Resultados Os graduandos demonstraram comprometimento em todas as fases do treinamento. Destaca-se, ainda, o interesse por assumirem a liderança em atividades práticas que redefinem seu perfil profissional. Essa experiência contribuiu para construir e nutrir relações intelectuais docentes-graduandos. Os graduandos expandiram suas redes profissionais e a relação com o mentor de carreira, estão desenvolvendo suas habilidades práticas e relataram confiança em se candidatar para cargos de assistentes de pesquisa. Conclusão e implicações para a prática O treinamento pode instrumentalizá-los para escolhas de planos de carreira, ingresso no mercado de trabalho e a construção de plano para desenvolvimento profissional. O desejo genuíno dos docentes de Enfermagem, apoiando uma nova geração de enfermeiros, culminou nessa experiência de empoderamento mútuo.

Resumen Objetivos Informar sobre la experiencia de un equipo de profesionales de enfermería y desarrollo profesional en la implementación de un programa de asistente voluntario de investigación para estudiantes universitarios canadienses de pregrado en enfermería con el objetivo de desarrollar la comunicación escrita y verbal, métodos de investigación, análisis de datos, pensamiento crítico y habilidades de resolución de problemas, así como en su planificación y avance profesional para funciones relacionadas con la investigación y oportunidades de empleo administrativo y de liderazgo. Método Un diseño descriptivo con el informe de la experiencia de los investigadores de enfermería y desarrollo profesional sobre el proceso de apoyo para la formación de los estudiantes para un nuevo rol profesional. La experiencia se refiere a 11 talleres que durarán una hora sobre los temas relacionados con la investigación. Resultados Los estudiantes demostraron compromiso con la capacitación. Relevante es su interés en liderar actividades prácticas para redefinir su perfil profesional. Esta experiencia contribuyó a construir y fomentar relaciones significativas e intelectuales entre los profesores y los estudiantes. Los estudiantes amplían sus redes profesionales y obtienen una relación con un mentor de carrera. Conclusión e implicaciones para la práctica La capacitación puede equipar mejor a los estudiantes para elegir trayectorias profesionales, entrar en el mercado laboral y elaborar un plan para el avance profesional. Fue el deseo genuino de los profesores de enfermería de apoyar a una nueva generación de enfermeras que culminó en esta experiencia de empoderamiento mutuo.

Abstract Objective To describe the experience of implementing a research assistant program for Canadian undergraduate nursing students, which aimed to develop written and verbal communication, critical thinking and problem-solving skills, as well as knowledge of various research methods. Engagement in this program was intended to support students' career planning and advancement in research related roles, including administrative and leadership employment opportunities. Method A descriptive design with the report of experience of nursing researchers and career advisers pertaining to: engagement in an 11 one-hour research focused workshop; and the process of supporting students to assume professional and leadership roles. Results Students demonstrated commitment to the training program throughout its phases. They expressed interest in leading practical activities to redefine their professional profile. This experience contributed to building and nurturing intellectual teacher-student relationships. Students are expanding their professional networks and a relationship with a career mentor, while demystifying the research assistant role. Students are developing practical skills and reporting confidence in applying for research assistant positions. Conclusion and Implications for practice Participating in the training program better equips students for choosing their career path, entering the job market, and building a plan for further career advancement. Nursing faculty's genuine desire for and purposeful actions to support a new generation of nurses informed this mutually empowering experience.

A Novel Cell-Penetrating Antibody Fragment Inhibits the DNA Repair Protein RAD51.

DNA damaging chemotherapies are successful in cancer therapy, however, the damage can be reversed by DNA repair mechanisms that may be up-regulated in cancer cells. We hypothesized that inhibiting RAD51, a protein involved in homologous recombination DNA repair, would block DNA repair and restore the effectiveness of DNA damaging chemotherapy. We used phage-display to generate a novel synthetic antibody fragment that bound human RAD51 with high affinity (KD = 8.1 nM) and inhibited RAD51 ssDNA binding in vitro. As RAD51 is an intracellular target, we created a corresponding intrabody fragment that caused a strong growth inhibitory phenotype on human cells in culture. We then used a novel cell-penetrating peptide "iPTD" fusion to generate a therapeutically relevant antibody fragment that effectively entered living cells and enhanced the cell-killing effect of a DNA alkylating agent. The iPTD may be similarly useful as a cell-penetrating peptide for other antibody fragments and open the door to numerous intracellular targets previously off-limits in living cells.

Genetic diversity of tumors with mismatch repair deficiency influences anti-PD-1 immunotherapy response.

Tumors with mismatch repair deficiency (MMR-d) are characterized by sequence alterations in microsatellites and can accumulate thousands of mutations. This high mutational burden renders tumors immunogenic and sensitive to programmed cell death-1 (PD-1) immune checkpoint inhibitors. Yet, despite their tumor immunogenicity, patients with MMR-deficient tumors experience highly variable responses, and roughly half are refractory to treatment. We present experimental and clinical evidence showing that the degree of microsatellite instability (MSI) and resultant mutational load, in part, underlies the variable response to PD-1 blockade immunotherapy in MMR-d human and mouse tumors. The extent of response is particularly associated with the accumulation of insertion-deletion (indel) mutational load. This study provides a rationale for the genome-wide characterization of MSI intensity and mutational load to better profile responses to anti-PD-1 immunotherapy across MMR-deficient human cancers.

Immunogenic neoantigens derived from gene fusions stimulate T cell responses.

Anti-tumor immunity is driven by self versus non-self discrimination. Many immunotherapeutic approaches to cancer have taken advantage of tumor neoantigens derived from somatic mutations. Here, we demonstrate that gene fusions are a source of immunogenic neoantigens that can mediate responses to immunotherapy. We identified an exceptional responder with metastatic head and neck cancer who experienced a complete response to immune checkpoint inhibitor therapy, despite a low mutational load and minimal pre-treatment immune infiltration in the tumor. Using whole-genome sequencing and RNA sequencing, we identified a novel gene fusion and demonstrated that it produces a neoantigen that can specifically elicit a host cytotoxic T cell response. In a cohort of head and neck tumors with low mutation burden, minimal immune infiltration and prevalent gene fusions, we also identified gene fusion-derived neoantigens that generate cytotoxic T cell responses. Finally, analyzing additional datasets of fusion-positive cancers, including checkpoint-inhibitor-treated tumors, we found evidence of immune surveillance resulting in negative selective pressure against gene fusion-derived neoantigens. These findings highlight an important class of tumor-specific antigens and have implications for targeting gene fusion events in cancers that would otherwise be less poised for response to immunotherapy, including cancers with low mutational load and minimal immune infiltration.