Expression, purification, and characterization of diacylated Lipo-YcjN from Escherichia coli.

YcjN is a putative substrate-binding protein expressed from a cluster of genes involved in carbohydrate import and metabolism in Escherichia coli. Here, we determine the crystal structure of YcjN to a resolution of 1.95 Å, revealing that its three-dimensional structure is similar to substrate binding proteins in subcluster D-I, which includes the well-characterized maltose binding protein (MBP). Furthermore, we found that recombinant overexpression of YcjN results in the formation of a lipidated form of YcjN that is posttranslationally diacylated at cysteine 21. Comparisons of size-exclusion chromatography profiles and dynamic light scattering measurements of lipidated and non-lipidated YcjN proteins suggest that lipidated YcjN aggregates in solution via its lipid moiety. Additionally, bioinformatic analysis indicates that YcjN-like proteins may exist in both Bacteria and Archaea, potentially in both lipidated and non-lipidated forms. Together, our results provide a better understanding of the aggregation properties of recombinantly expressed bacterial lipoproteins in solution and establish a foundation for future studies that aim to elucidate the role of these proteins in bacterial physiology.

Hamstrings on focus: Are 72 hours sufficient for recovery after a football (soccer) match? A multidisciplinary approach based on hamstring injury risk factors and histology.

This study aimed to assess acute and residual changes in sprint-related hamstring injury (HSI) risk factors after a football (soccer) match, focusing on recovery within the commonly observed 72-h timeframe between elite football matches. We used a multifactorial approach within a football context, incorporating optical and ultrastructural microscopic analysis of BFlh (biceps femoris long head) muscle fibres, along with an examination of BFlh fibre composition. Changes in sprint performance-related factors and HSI modifiable risk factors were examined until 3 days after the match (MD +3) in 20 football players. BFlh biopsy specimens were obtained before and at MD +3 in 10 players. The findings indicated that at MD +3, sprint-related performance and HSI risk factors had not fully recovered, with notable increases in localized BFlh fibre disruptions. Interestingly, match load (both external and internal) did not correlate with changes in sprint performance or HSI risk factors nor with BFlh fibre disruption. Furthermore, our study revealed a balanced distribution of ATPase-based fibre types in BFlh, with type-II fibres associated with sprint performance. Overall, the results suggest that a 72-h recovery period may not be adequate for hamstring muscles in terms of both HSI risk factors and BFlh fibre structure following a football match.

Ovarian Sex Cord Stromal Tumor in a Free-Ranging Brown Bear (Ursus arctos).

Reports on neoplasms in bears are scarce, especially concerning ovarian tumors. A large primary ovarian neoplasm with multiple metastasis was found during the necropsy of a 14-year-old free-ranging Eurasian brown bear (Ursus arctos) from Northwestern Spain. Histopathology and immunohistochemistry allowed for the diagnosis of a sex cord stromal tumor. This is a complex group of neoplasms which differ in the predominant cell morphology and immunohistochemical features. The microscopic examination revealed two types of cells, one with eosinophilic cytoplasm, intermingled with larger vacuolated cells rich in lipids. The evaluation of the immunoreactivity to different markers, frequently used in the characterization of gonadal tumors (INHA, inhibin-alpha; PLAP, placental alkaline phosphatase; Ki-67; α-SMA, actin alpha-smooth muscle) and inflammation patterns (IBA1, ionized calcium-binding adapter molecule for macrophages; CD3 for T lymphocytes; CD20 for B lymphocytes), displayed significant INHA positive immunostaining of neoplastic cells, as well as inflammatory cell infiltration, mainly composed of macrophages and B lymphocytes. These findings were consistent with a malignant ovarian steroid cell tumor, not otherwise specified. The present study characterizes an unusual type of neoplasm, and also represents the first report of an ovarian sex cord stromal tumor in Ursidae.

Structural insights reveal interplay between LAG-3 homodimerization, ligand binding, and function.

Lymphocyte activation gene-3 (LAG-3) is an inhibitory receptor expressed on activated T cells and an emerging immunotherapy target. Domain 1 (D1) of LAG-3, which has been purported to directly interact with major histocompatibility complex class II (MHCII) and fibrinogen-like protein 1 (FGL1), has been the major focus for the development of therapeutic antibodies that inhibit LAG-3 receptor-ligand interactions and restore T cell function. Here, we present a high-resolution structure of glycosylated mouse LAG-3 ectodomain, identifying that cis-homodimerization, mediated through a network of hydrophobic residues within domain 2 (D2), is critically required for LAG-3 function. Additionally, we found a previously unidentified key protein-glycan interaction in the dimer interface that affects the spatial orientation of the neighboring D1 domain. Mutation of LAG-3 D2 residues reduced dimer formation, dramatically abolished LAG-3 binding to both MHCII and FGL1 ligands, and consequentially inhibited the role of LAG-3 in suppressing T cell responses. Intriguingly, we showed that antibodies directed against D1, D2, and D3 domains are all capable of blocking LAG-3 dimer formation and MHCII and FGL-1 ligand binding, suggesting a potential allosteric model of LAG-3 function tightly regulated by dimerization. Furthermore, our work reveals unique epitopes, in addition to D1, that can be targeted for immunotherapy of cancer and other human diseases.

Clinical, Epidemiologic, and Pathologic Significance of ERBB2-Low Expression in Breast Cancer.

Importance: It is unclear whether breast cancer (BC) with low ERBB2 expression (ERBB2-low) is a distinct clinical, pathological, and epidemiological entity from BC classified as no ERBB2 expression (ERBB2-negative). Objective: To evaluate the clinical, pathological, and epidemiologic features of BC with ERBB2-low expression compared with ERBB2-negative BC in a large population study. Design, Setting, and Participants: This cohort study was conducted as part of the Pathways Study, a prospective, racially and ethnically diverse cohort study of women with BC enrolled between 2006 and 2013 in Kaiser Permanente Northern California (KPNC). The hematoxylin and eosin slides underwent centralized pathology review, including the percentage of tumor infiltrating lymphocytes (TILs). Breast biomarker results were extracted from pathology reports, and women were included if they had a documented ERBB2 value that was not classified ERBB2-positive. Data were analyzed from February 2023 through January 2024. Exposure: Clinical and tumor characteristics associated with BC and ERBB2-low or ERBB2-negative status. Main Outcome and Measures: ERBB2-low was defined as immunohistochemistry score of 1+ or 2+ (negative by in situ hybridization); ERBB2-negative was defined as immunohistochemistry score of 0+. Other data were collected by self-report or extraction from electronic health records, including BC risk factors, tumor characteristics, treatment modality, and survival outcomes, with recurrence-free survival (RFS) as the primary outcome and overall survival (OS) and BC-specific mortality (BCSM) as secondary outcomes. The clinical, pathological, and epidemiological variables were compared between ERBB2-low and ERBB2-negative BC. Results: Of 2200 eligible patients (all female; with mean [SD] age, 60.4 [11.9] years), 1295 (57.2%) had tumors that were ERBB2-low. Hormone receptors were positive in 1956 patients (88.9%). The sample included 291 Asian patients (13.2%), 166 Black patients (7.5%), 253 Hispanic patients (11.5%), 1439 White patients (65.4%), and 51 patients (2.3%) who identified as other race or ethnicity (eg, American Indian or Alaska Native and Pacific Islander). Within the hormone receptor-negative group, patients whose tumors had ERBB2-low staining, compared with those with ERBB2-negative tumors, had better OS (hazard ratio [HR], 0.54; 95% CI, 0.33-0.91; P = .02), RFS (HR, 0.53; 95% CI, 0.30-0.95; P = .03), and BCSM (HR, 0.43; 95% CI, 0.22-0.84; P = .01). In multivariable survival analysis stratified by hormone receptor status and adjusted for key covariates, patients with ERBB2-low and hormone receptor-negative tumors had lower overall mortality (HR, 0.48; 95% CI, 0.27-0.83; P = .009), RFS (HR, 0.45; 95% CI, 0.24-0.86; P = .02), and BCSM (subdistribution HR, 0.21; 95% CI, 0.10-0.46; P < .001) compared with patients with ERBB2-negative and hormone receptor-negative tumors. Within the hormone receptor-negative subtype, patients with ERBB2-low and high TILs tumors had better survival across all 3 outcomes compared with patients with ERBB2-negative and low TILs tumors. Additionally, patients with ERBB2-low and low TILs tumors had better BCSM (subdistribution HR, 0.36; 95% CI, 0.14-0.92; P = .03). Conclusions and Relevance: These findings suggest that there were clinical, pathological, and epidemiological differences between ERBB2-low and ERBB2-negative BC, raising the possibility that ERBB2-low might be a unique biologic entity.

Development and Psychometric Validation of the Breast Cancer Stigma Assessment Scale for Women with Breast Cancer and Its Survivors.

BACKGROUND: The increase in breast cancer cases and breast cancer survival makes it advisable to quantify the impact of the health-related stigma of this disease. PURPOSE/OBJECTIVES: To develop and validate a breast cancer stigma scale in Spanish. METHODS: Women diagnosed with, or survivors of, breast cancer were included. The development of the Breast Cancer Stigma Assessment Scale (BCSAS) involved both a literature review and personal interviews. Content validity was assessed using a Delphi study and a pilot test; construct validity was evaluated using an exploratory factor analysis; and convergent validity was assessed using six scales. Cronbach's α internal consistency and test-retest reliability were used to determine the reliability of the scales. RESULTS: 231 women responded to the 28-item scale. The BCSAS showed good reliability, with α = 0.897. Seven factors emerged: concealment (α = 0.765), disturbance (α = 0.772), internalized stigma (α = 0.750), aesthetics (α = 0.779), course (α = 0.599), danger (α = 0.502), and origin (α = 0.350). The test-retest reliability was 0.830 (p < 0.001). Significant correlation was observed with event centrality (r = 0.701), anxiety-depression (r = 0.668), shame (r = 0.645), guilt (r = 0.524), and quality of life (r = -0.545). CONCLUSIONS: The BCSAS is a reliable and valid measure of stigma in women with breast cancer and its survivors. It could be useful for detecting stigma risk and establishing psychotherapeutic and care priorities.

Targeting Aspergillus allergen oryzin with a chemical probe at atomic precision.

We report the molecular basis of Aspergillus fumigatus oryzin, allergen Asp f 13, or alkaline proteinase ALP1, containing the sequence motif His-Asp-Ser of the subtilisin family, structure, and function at atomic detail. Given the resolution of the data (1.06 Å), we use fragment molecular replacement with ideal polyalanine α-helices to determine the first crystal structure of oryzin. We probe the catalytic serine through formation of an irreversible bond to a small molecule compound, specifically labeling it, describing the amino acid residues performing the catalytic function. Defined by a self-processed pro-peptide, the active site architecture shapes up pocket-like subsites that bind to and unveil the S1'-S4' substrate binding preferences. We use molecular modeling to dock a model of the pro-peptide in the S1-S4 region and to dock collagen along the active site cleft. Opposite to the face harboring the catalytic serine, the enzyme binds to a calcium ion in a binding site created by backbone flipping. We use thermal unfolding to show that this metal ion provides structural stability. With no known host inhibitor identified thus far, this structure may hasten the progress of developing new therapeutic agents for diseases caused by pathogenic fungi.

Candidatus Neoehrlichia mikurensis Infection in Patient with Antecedent Hematologic Neoplasm, Spain1.

We report a confirmed case of Candidatus Neoehrlichia mikurensis infection in a woman in Spain who had a previous hematologic malignancy. Candidatus N. mikurensis infections should be especially suspected in immunocompromised patients who exhibit persistent fever and venous thrombosis, particularly if they live in environments where ticks are prevalent.

Quality of dying among elderly people diagnosed with dementia in nursing homes: A mixed methods study.

WHAT IS KNOWN ON THE SUBJECT: Nurses working at nursing homes can play a pivotal role in mental health as a high proportion of residents diagnosed with dementia are in these facilities. Many institutionalized residents diagnosed with dementia develop clinical complications and symptoms that reduce the quality of dying. A mixed-methods approach can help nurses with the difficult task of assessing the quality of dying among these residents and identify inconsistencies that cannot be found using scales alone, but no studies were found in this topic. WHAT THE PAPER ADDS TO EXISTING KNOWLEDGE: Through the Quality of dying in Long-Term Care Scale (QoD-LTC), nurses described symptom management, quality of care, and end-of-life appearance as adequate and end-of-life communication as lacking. Generally speaking, the scores on the scale were consistent with the data from semi-structured interviews conducted with nurses. In the semi-structured interviews, some of the concepts on the scale, including 'dignity', 'holistic' care, 'good relationships with healthcare professionals', and 'a peaceful death', are complex and not fully incorporated into nurses' practice in nursing homes when assessing residents diagnosed with dementia. This could be improved by using the SENSES Model or person-centred care frameworks. WHAT ARE THE IMPLICATIONS FOR PRACTICE?: There is evidence of shortcomings among professionals in the correct use of concepts linked to psychological wellbeing, communication, therapeutic relationship, safety and participation, preservation of dignity, decision-making, and resident autonomy, which can be addressed using specific theoretical approaches developed in the field of mental health nursing. ABSTRACT: Introduction The complex nature of end-of-life assessment of individuals diagnosed with dementia would benefit from a mixed-methods approach that simultaneously assess the perception and response of nurses to standardized tools. Aim/Question To examine nursing professionals' perceptions of the quality of dying among residents diagnosed with dementia using the Quality of Dying in Long-Term Care settings (QoD-LTC) questionnaire and to identify consistencies and inconsistencies in their narratives. Method Mixed-methods study using concurrent triangulation with data integration for results and interpretation. Nurses from eight nursing homes assessed 117 residents diagnosed with dementia who died in the previous 3 months using the QoD-LTC scale. After informed consent was obtained (nurses/caregivers), 17 semi-structured scale-based interviews were conducted. Results Symptom management, quality of care, and end-of-life appearance were found to be adequate, while end-of-life communication was deemed insufficient. The qualitative and quantitative data were consistent for most of the items on the QoD-LTC. Discussion Concepts such as dignity, holistic care, good relationships, and peaceful death are complex and not fully incorporated into professional practice. Implications for Practice The results highlight the need for greater involvement of mental health nurses as well as improved communication, training, and specific tools tailored to residents diagnosed with dementia.

Identifying and overcoming barriers to participation of minority populations in clinical trials: Lessons learned from the VanDAAM study.

Participation in cancer research trials by minority populations is imperative in reducing disparities in clinical outcomes. Even with increased awareness of the importance of minority patient inclusion in clinical research to improve cancer care and survival, significant barriers persist in accruing and retaining minority patients into clinical trials. This study sought to identify and address barriers to minority accrual to a minimal risk clinical research study in real-time.

Acid-base potentiometric titration using a stainless steel electrode without oxidative treatment.

An AISI 304 stainless steel laminar electrode without oxidative treatment was investigated for the potentiometric titration of hydrochloric acid with sodium hydroxide. The proposed electrode was obtained from metalworking cuttings. Scanning electron microscopy, energy dispersive X-ray spectroscopy, X-ray fluorescence spectroscopy and X-ray diffraction were used to study the surface morphology and chemical composition of the electrode. The electrode showed a sensitivity of 59.18 ± 0.37 mV/pH, which was reproducible under intermediate conditions. Potentiometric titration showed a curve with deviations from pH 9.5 with respect to the glass electrode. However, this did not affect the quantification as the jumps of the curves coincided. The endpoint was 9.25 mL for both electrodes and the hydrochloric acid concentration was 0.0845 mol/L, with a deviation of 0.0004 mol/L from the standard concentration of 0.0841 mol/L. The nonartificially oxidised electrode did not show any crystalline oxide phases, whereas after oxidation it showed semicrystalline phases of iron and chromium oxides and increased the crystallinity of the steel. Despite the low content of surface oxides, stainless steel electrodes can give a Nernstian response to pH, depending on the surface characteristics of the material. This leads to the need to calibrate any electrode prior to oxidative treatment to rule out a Nernstian response without surface modification.

¿Los pacientes odontológicos están dispuestos a pagar por medidas de bioseguridad ante COVID-19? Variaciones en el tipo de tratamiento y la presencia de comorbilidades / ¿Are dental patients willing to pay for biosecurity measures against COVID-19? Variations in the type of treatment and the presence of comorbidities

Resumen Objetivo: Estimar si los pacientes odontológicos están dispuestos a pagar (DAP) más por sus citas sabiendo que la clínica donde asisten implementó medidas de bioseguridad para evitar el contagio del COVID-19. De igual manera, si dicho pago varía dependiendo del tipo de tratamiento odontológico, así como si el paciente presenta algún tipo de comorbilidad. Materiales y métodos: Desarrollo y aplicación de encuestas en línea a una muestra de 423 pacientes odontológicos en México con diferentes tratamientos y presencia de comorbilidad si estuvieran dispuestos a pagar por su atención ante la emergencia COVID por las medidas de bioseguridad utilizando un análisis estadístico de medias. La encuesta se aplicó en los meses de septiembre a noviembre de 2020. Resultados: Se estimó que aproximadamente el 32% cancelaría sus citas dentales por miedo a contraer COVID-19; sin embargo, casi un 45% estarían DAP un monto extra en la cita, si el consultorio o clínica implementa estrictas medidas de bioseguridad. Estos porcentajes, tanto de la cancelación de cita, como de la disponibilidad a pagar adicional, se incrementa si el paciente presenta alguna comorbilidad. Conclusiones: Los pacientes de la muestra están dispuestos a pagar un monto excedente por sus citas sabiendo que los consultorios implementaron medidas de bioseguridad, y más si son pacientes que presentan alguna comorbilidad. Así mismo, dichos consultorios podrían recibir algún apoyo del Gobierno para el bienestar de toda la sociedad.

Abstract Objective: Estimate whether dental patients are willing to pay (DAP) more for their appointments knowing that the clinic where they attend implemented biosecurity measures to prevent the spread of COVID-19. Similarly, if said payment varies depending on the type of dental treatment, as well as if the patient has some type of comorbidity. Materials and methods: Development and application of online surveys to a sample of 423 dental patients in Mexico with different treatments and presence of comorbidity if they were willing to pay for their care in the face of the COVID emergency for biosecurity measures using a statistical analysis of means . The survey was applied in the months of September to November 2020. Results: It was estimated that approximately 32% would cancel their dental appointments for fear of contracting COVID-19; however, almost 45% would be DAP an extra amount in the appointment, if the office or clinic implements strict biosecurity measures. These percentages, both for appointment cancellation and willingness to pay additional, are increased if the patient has any comorbidity. Conclusions: The patients in the sample are willing to pay an excess amount for their appointments knowing that the offices have implemented biosafety measures, and more so if they are patients with some comorbidity. Likewise, these clinics could receive some support from the Government for the well-being of the entire society.

Genomic Testing in Localized Prostate Cancer Can Identify Subsets of African Americans With Aggressive Disease.

BACKGROUND: Personalized genomic classifiers have transformed the management of prostate cancer (PCa) by identifying the most aggressive subsets of PCa. Nevertheless, the performance of genomic classifiers to risk classify African American men is thus far lacking in a prospective setting. METHODS: This is a prospective study of the Decipher genomic classifier for National Comprehensive Cancer Network low- and intermediate-risk PCa. Study-eligible non-African American men were matched to African American men. Diagnostic biopsy specimens were processed to estimate Decipher scores. Samples accrued in NCT02723734, a prospective study, were interrogated to determine the genomic risk of reclassification (GrR) between conventional clinical risk classifiers and the Decipher score. RESULTS: The final analysis included a clinically balanced cohort of 226 patients with complete genomic information (113 African American men and 113 non-African American men). A higher proportion of African American men with National Comprehensive Cancer Network-classified low-risk (18.2%) and favorable intermediate-risk (37.8%) PCa had a higher Decipher score than non-African American men. Self-identified African American men were twice more likely than non-African American men to experience GrR (relative risk [RR] = 2.23, 95% confidence interval [CI] = 1.02 to 4.90; P = .04). In an ancestry-determined race model, we consistently validated a higher risk of reclassification in African American men (RR = 5.26, 95% CI = 1.66 to 16.63; P = .004). Race-stratified analysis of GrR vs non-GrR tumors also revealed molecular differences in these tumor subtypes. CONCLUSIONS: Integration of genomic classifiers with clinically based risk classification can help identify the subset of African American men with localized PCa who harbor high genomic risk of early metastatic disease. It is vital to identify and appropriately risk stratify the subset of African American men with aggressive disease who may benefit from more targeted interventions.

Respiratory pathogens in children with acute lower respiratory infection detected through multiplex real-time PCR / Patógenos respiratorios en niños con infección respiratoria aguda baja detectados mediante PCR multiplex en tiempo real

Abstract Introduction: Acute respiratory infection in children has a high burden of disease. Detection of multiple micro -organisms through molecular testing of nasopharyngeal swab samples could change the paradigm of a single pathogen being the cause of respiratory disease in children and prove its usefulness in clinical practice. Objective: To characterize the pathogens identified in nasopharyngeal swab samples by means of multiplex realtime polymerase chain reaction (RT-PCR), as well as clinical variables and laboratory findings in children <5 years diagnosed with acute lower respiratory tract infection (ALRTI) and hospitalized in Bogotá D.C., Colombia. Materials and methods: Cross-sectional study conducted in 81 children hospitalized between September 2019 and March 2020 at the Clínica Cafam and in whom nasopharyngeal swab samples were collected for microbiological identification using the Allplex™ multiplex RT-PCR assay. Correlations between the number of pathogens and blood cells and C-reactive protein levels were determined by Spearman's rank correlation coefficient. Results: Patients' mean age was 17.23 months (±14.44), 54.32% were males, and 51.85% were young infants. A total of 149 microorganisms (60.40% viruses) were identified in 63 children (77.78%). Mixed infection and coinfection were reported in 48.15% and 11.11% of children, respectively. Regarding clinical findings, shortness of breath, upper airway obstruction, cough, fever and pharyngitis were the most common clinical signs and/or symptoms in patients with mixed infection (32.97%), coinfection (64.40%), mixed infection (29.78%), and absence of microorganism (22.00%), respectively. A negative correlation was observed between the number of leukocytes and the number of neutrophils and the number of microorganisms detected in the preschoolers group (r=-0.46; p =0.058 and r=-0.51; p =0.033, respectively). Furthermore, a positive correlation was found between monocyte count and the number of microorganisms detected (r=0.53; p =0.0096). Conclusion: Multiplex RT-PCR assay allowed the identification of microorganisms in most children, as well as cases of mixed infection and coinfection in more than half of the sample. In addition, clinical findings in these children were highly heterogeneous as per the assay result..

Resumen Introducción. La infección respiratoria aguda en niños tiene una alta carga de enfermedad. La detección de múltiples microorganismos a través de pruebas moleculares en hisopados nasales podría cambiar el paradigma de patógeno único causal de enfermedad respiratoria en niños y ser de utilidad en la práctica clínica. Objetivo. Caracterizar los patógenos identificados mediante la técnica de reacción en cadena de polimerasa multiplex en tiempo real (RT-PCR) en hisopado nasal, así como las variables clínicas y los resultados de laboratorio en niños <5 años diagnosticados con infección respiratoria aguda baja (IRAB) y hospitalizados en Bogotá D.C., Colombia. Materiales y métodos. Estudio transversal realizado en 81 niños hospitalizados entre septiembre de 2019 y marzo de 2020 en la clínica Cafam y en quienes se hizo hisopado nasal para realizar la identificación microbiològica mediante la prueba RT-PCR multiplex Allplex. Las correlaciones entre el número de patógenos y los niveles de células del hemograma y el nivel de proteína C reactiva se determinaron mediante el coeficiente de correlación de Spearman. Resultados. La edad promedio fue 17.23 meses (±14.44), 54.32% fueron varones y 51.85%, lactantes menores. Se identificaron 149 microorganismos (60.40% virus) en 63 niños (77.78%). Hubo infección mixta en el 48.15% y coinfección en 11.11% de los niños. Respecto a los hallazgos clínicos, la dificultad respiratoria, la obstrucción de la vía respiratoria alta, la tos, la fiebre y la faringitis fueron más comunes en los casos de infección mixta (32.97%), ausencia de microorganismo (16.00%), coinfección (64.40%), infección mixta (29.78%) y ausencia de microorganismo (22.00%), respectivamente. Se observó una correlación negativa entre el número de leucocitos y neutrófilos y el número de microorganismos detectados en preescolares (r=-0.46; p=0.058 y r=-0.51; p=0.033) y una positiva entre el recuento de monocitos y el número de microorganismos detectados (r=0.53; p =0.0096). Conclusión. La prueba RT-PCR multiplex permitió identificar microorganismos en la mayoría de niños, así como casos de infección mixta y coinfección en más de la mitad de la muestra. Además, los hallazgos clínicos fueron altamente heterogéneos entre los niños según el resultado de la prueba.

Novel portable apparatus for outpatient high-dose-rate (HDR) brachytherapy in penile cancer.

BACKGROUND: Penile squamous cell carcinoma (PSC) is traditionally treated with surgical resection with significant morbidity. Penile sparing approaches, such as brachytherapy, require expertise, prolonged inpatient stays, poor patient convenience, and heterogenous plans with variable long-term toxicity. In this study, we describe the protocol for novel portable apparatus created for PSC, allowing outpatient hybrid interstitial/surface brachytherapy, improving homogeneity and patient convenience. METHODS: A portable brachytherapy apparatus was developed utilizing a foley catheter, prostate template, 6F interstitial catheters, 5 mm bolus, and a jock strap. The apparatus allowed for internal and external catheter placement housed in a jock strap to allow mobility and defecation without affecting the implant. High-dose-rate brachytherapy was performed as an outpatient. RESULTS: The apparatus was then used on a 62-year-old male with cT2pN0M0 (stage IIA) PSC with bilateral glans and urethral meatus involvement, who elected for definitive brachytherapy (4000cGy in 10 fractions over 5-days). Given external dwell positions, heterogeneity correction of the template was calculated (AAPM TG186) with <2% variation. Patient had minimal impact on his active lifestyle during treatment and had complete clinical response at 3-months. Grade 2 skin desquamation resolved at 2-months, with no necrosis. At 6-months, he was able to resume sexual intercourse, and at 12-months, he remained disease-free with sexual and urinary function intact. CONCLUSIONS: Novel portable implant allows for improved patient convenience, reduced inpatient stay, capable of optimizing dosimetry with hybrid brachytherapy. This outpatient treatment allows the opportunity to increase fractionation, offering high local-control and lower toxicity. Future studies utilizing this apparatus for more fractionated regimens with further lower dose-per-fraction (∼3 Gy/fraction) is recommended.

Targeting colorectal cancer with small-molecule inhibitors of ALDH1B1.

Aldehyde dehydrogenases (ALDHs) are promising cancer drug targets, as certain isoforms are required for the survival of stem-like tumor cells. We have discovered selective inhibitors of ALDH1B1, a mitochondrial enzyme that promotes colorectal and pancreatic cancer. We describe bicyclic imidazoliums and guanidines that target the ALDH1B1 active site with comparable molecular interactions and potencies. Both pharmacophores abrogate ALDH1B1 function in cells; however, the guanidines circumvent an off-target mitochondrial toxicity exhibited by the imidazoliums. Our lead isoform-selective guanidinyl antagonists of ALDHs exhibit proteome-wide target specificity, and they selectively block the growth of colon cancer spheroids and organoids. Finally, we have used genetic and chemical perturbations to elucidate the ALDH1B1-dependent transcriptome, which includes genes that regulate mitochondrial metabolism and ribosomal function. Our findings support an essential role for ALDH1B1 in colorectal cancer, provide molecular probes for studying ALDH1B1 functions and yield leads for developing ALDH1B1-targeting therapies.

Análisis estadístico de los factores de riesgo asociados a las patologías de la columna lumbar para la población empleada / Statistical analysis of risk factors associated with lumbar spine pathologies for the employed population

Objetivo: Determinar los factores de riesgo de patologías lumbares en pacientes empleados y afiliados al sistema de salud, a partir de la exploración física, hábitos, antecedentes personales y factores de riesgo laborales. Material y Métodos: El diseño del estudio es retrospectivo, transversal. En una muestra de 668 adultos trabajadores del Ecuador, se aplicó y evaluó el modelo predictivo de respuesta binaria logit para identificar factores de riesgo y se usaron métodos de aprendizaje supervisado (árboles de clasificación) para clasificar a los pacientes según el grado de patología lumbar. Resultados: El modelo predictivo logístico presentó una sensibilidad del 62,5%, una especificidad del 63,7%, el área bajo la curva ROC fue 0,63 y se determinó una precisión del 63,4%.Conclusión: Los factores que aumentan el riesgo de la patología de columna lumbar más frecuente (lumbalgia) y en orden de importancia en los pacientes son: menor edad, sexo femenino, tienden a exponerse a factores de riesgo psicosocial en su trabajo

Objective: Determine the risk factors of lumbar pathologies in patients employed and affi-liated with the health system, based on physical examination, habits, personal history, and occupational risk factors.Materials and Methods: The study design is retrospective, cross-sectional. In a sample of 668 adult workers from Ecuador. The binary logit response predictive model was applied to identify risk factors and supervised learning methodology (classification trees) was used to classify patients according to the degree of lumbar pathology.Results: The logistic predictive model has a sensitivity of 62.5%, a specificity of 63.7%, the area under the ROC curve was 0.63, and precision of 63.4% was determined.Conclusion: The factors that increase the risk of the most frequent lumbar pathology (low back pain) in order of importance in patients are: younger age, female sex, tend to be expo-sed to psychosocial risk factors at work, and lower risk of having mechanical factors.

ENPP1's regulation of extracellular cGAMP is a ubiquitous mechanism of attenuating STING signaling.

The metazoan innate immune second messenger 2'3'-cGAMP is present both inside and outside cells. However, only extracellular cGAMP can be negatively regulated by the extracellular hydrolase ENPP1. Here, we determine whether ENPP1's regulation of extracellular cGAMP is a ubiquitous mechanism of attenuating stimulator of interferon genes (STING) signaling. We identified ENPP1H362A, a point mutation that cannot degrade the 2'-5' linkage in cGAMP while maintaining otherwise normal function. The selectivity of this histidine is conserved down to bacterial nucleotide pyrophosphatase/phosphodiesterase (NPP), allowing structural analysis and suggesting an unexplored ancient history of 2'-5' cyclic dinucleotides. Enpp1H362A mice demonstrated that extracellular cGAMP is not responsible for the devastating phenotype in ENPP1-null humans and mice but is responsible for antiviral immunity and systemic inflammation. Our data define extracellular cGAMP as a pivotal STING activator, identify an evolutionarily critical role for ENPP1 in regulating inflammation, and suggest a therapeutic strategy for viral and inflammatory conditions by manipulating ENPP1 activity.