The aryl hydrocarbon receptor and FOS mediate cytotoxicity induced by Acinetobacter baumannii.

Acinetobacter baumannii is a pathogenic and multidrug-resistant Gram-negative bacterium that causes severe nosocomial infections. To better understand the mechanism of pathogenesis, we compare the proteomes of uninfected and infected human cells, revealing that transcription factor FOS is the host protein most strongly induced by A. baumannii infection. Pharmacological inhibition of FOS reduces the cytotoxicity of A. baumannii in cell-based models, and similar results are also observed in a mouse infection model. A. baumannii outer membrane vesicles (OMVs) are shown to activate the aryl hydrocarbon receptor (AHR) of host cells by inducing the host enzyme tryptophan-2,3-dioxygenase (TDO), producing the ligand kynurenine, which binds AHR. Following ligand binding, AHR is a direct transcriptional activator of the FOS gene. We propose that A. baumannii infection impacts the host tryptophan metabolism and promotes AHR- and FOS-mediated cytotoxicity of infected cells.

Two Decades of Thyroid Nodule Cytology in Children: Malignancy Risk Assessment at a Tertiary Care Center.

INTRODUCTION: Pediatric thyroid nodules exhibit higher malignancy rates compared to adults and are associated with increased incidences of metastases and recurrences. The American Thyroid Association recommends surgery for indeterminate thyroid biopsies in children based on these higher malignancy risks, though this approach may lead to overtreatment. However, there remains a lack of comprehensive pediatric data to inform clinical decisions. This study examines the risk of malignancy (ROM) in pediatric thyroid nodules using the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) and assesses the diagnostic accuracy of fine-needle aspiration (FNA) biopsy compared to histological outcomes. METHODS: A retrospective cross-sectional analysis was performed on patients under 19 years with thyroid nodules who underwent FNA and thyroidectomy at a tertiary care center. The sensitivity, specificity, positive predictive value, negative predictive value, and ROM of cytological biopsies were evaluated using TBSRTC criteria, with histology serving as the gold standard. Two analyses were conducted to assess diagnostic accuracy: (a) TBSRTC II as negative and TBSRTC VI as positive and (b) TBSRTC II as negative with TBSRTC V and VI as positive. For neoplasia detection, TBSRTC II was deemed negative, while TBSRTC IV, V, and VI were considered positive. TBSRTC categories III and I were excluded from the performance analysis and evaluated separately. Follicular neoplasm or lesions suspicious for follicular neoplasm (FN/SFN) were treated as positive outcomes, correlated with the presence of adenoma or carcinoma in the surgical specimen. RESULTS: Of 75 nodules from 73 patients, 28 (37.3%) were benign and 47 (62.6%) malignant. No significant differences in gender or age were noted between groups. The ROM in each TBSRTC was Bethesda I 0/2, 0%; II 0/13, 0%; III 2/7, 29%: IV 6/14, 43%; V 10/10, 100%, and VI 29/29, 100%. A sensitivity of 78.38% and specificity of 100% for FNA in detecting malignancy was found, with an even higher sensitivity (100%) for detecting neoplasia in TBSRTC IV. CONCLUSIONS: This study reveals that indeterminate thyroid nodules in pediatric patients exhibit a higher rate of malignancy compared to adults, yet align with rates previously reported in the pediatric population. These findings highlight the critical need for guidelines tailored specifically to the management of thyroid nodules and thyroid cancer in children.

Impact of obesity­associated myeloid­derived suppressor cells on cancer risk and progression (Review).

Obesity is a chronic disease caused by the accumulation of excessive adipose tissue. This disorder is characterized by chronic low­grade inflammation, which promotes the release of proinflammatory mediators, including cytokines, chemokines and leptin. Simultaneously, chronic inflammation can predispose to cancer development, progression and metastasis. Proinflammatory molecules are involved in the recruitment of specific cell populations in the tumor microenvironment. These cell populations include myeloid­derived suppressor cells (MDSCs), a heterogeneous, immature myeloid population with immunosuppressive abilities. Obesity­associated MDSCs have been linked with tumor dissemination, progression and poor clinical outcomes. A comprehensive literature review was conducted to assess the impact of obesity­associated MDSCs on cancer in both preclinical models and oncological patients with obesity. A secondary objective was to examine the key role that leptin, the most important proinflammatory mediator released by adipocytes, plays in MDSC­driven immunosuppression Finally, an overview is provided of the different therapeutic approaches available to target MDSCs in the context of obesity­related cancer.

Long-term remission of infantile Takayasu arteritis associated with germline CBL syndrome after allogeneic hematopoietic stem cell transplantation: A case report and literature review.

Takayasu arteritis (TA) is a large-vessel vasculitis that rarely presents in infancy. Casitas B-lineage lymphoma (CBL) syndrome is a rare genetic disorder due to heterozygous CBL gene germline pathogenic variants that is characterized by a predisposition to develop juvenile myelomonocytic leukemia (JMML). Vasculitis, including TA, has been reported in several patients. Herein, we describe a patient with CBL syndrome, JMML, and TA, developing long-term remission of this vasculitis after allogeneic hematopoietic stem cell transplant (HSCT), and perform a literature review of CBL syndrome with vasculitis or vasculopathy. We report a female patient with growth delay, developmental issues, and congenital heart disease who was admitted at 14 months of age with massive splenomegaly, lymphadenopathy, fever, and hypertension. Body imaging studies revealed arterial stenosis and wall inflammation of the aorta and multiple thoracic and abdominal branches. Whole exome sequencing revealed a pathogenic variant in CBL with loss of heterozygosity in blood cells, diagnosing CBL syndrome, complicated by JMML and TA. Allogeneic HSCT induced remission of JMML and TA, permitting discontinuation of immunosuppression after 12 months. Six years later, her TA is in complete remission off therapy. A literature review identified 18 additional cases of CBL syndrome with vasculitis or vasculopathy. The pathogenesis of vasculitis in CBL syndrome appears to involve dysregulated T cell function and possibly increased angiogenesis. This case advances the understanding of vascular involvement in CBL syndrome and of the genetic, immune, and vascular interplay in TA, offering insights for treating CBL syndrome and broader TA.

Checklist for studies of HIV drug resistance prevalence or incidence: rationale and recommended use.

HIV drug resistance (HIVDR) is a major challenge to the effectiveness of antiretroviral therapy. Global efforts in addressing HIVDR require clear, transparent, and replicable reporting in HIVDR studies. We describe the rationale and recommended use of a checklist that should be included in reports of HIVDR incidence and prevalence. After preliminary consultations with experts on HIVDR and establishing the need for guidance on HIVDR reporting, we used a sequential, explanatory, mixed methods approach to create the checklist; together with the accompanying articles, the checklist was reviewed by the authors and validated externally. The checklist for studies on HIVDR prevalence or incidence (CEDRIC-HIV) includes 15 recommended items that would enhance transparency and facilitate interpretation, comparability, and replicability of HIVDR studies. CEDRIC-HIV will help authors of HIVDR studies prepare research reports and assist reviewers and editors in assessments of completeness of reporting. The checklist will also facilitate statistical pooling and interpretation of HIVDR data.

Quality Variations in Thyrotropin Alfa.

Thyrotropin alfa is a heterodimeric glycoprotein containing human thyroid stimulating hormone (TSH). It is used as an adjunctive diagnostic tool for serum thyroglobulin (Tg) testing with or without radioiodine imaging in the follow-up of patients with well-differentiated thyroid cancer who have previously undergone thyroidectomy. Inter-lot variability in the Fourier transform near-infrared spectra of 30 samples obtained from four separate lots of Thyrogen® was detected in the Drug Quality Study (DQS). The vials fell into two distinct groups (rtst = 0.90, rlim= 0.98, p=0.02). In addition, one vial of the 30 (3%) appeared 4.7 multidimensional SDs from all of the other vials, suggesting that it also represents a different material.

Evaluating the Efficacy and Safety of Laparoscopic Heller Myotomy in Treating Achalasia

Introduction: Laparoscopic Heller myotomy (LHM) is widely recognized as the standard surgical treatment for esophageal achalasia. However, there is a lack of local data regarding the clinical characteristics of patients and the outcomes of this intervention. Methodology: This retrospective study analyzed patients who underwent LHM over an eight-year period. Demographic, operative, and postoperative variables were assessed. The Eckardt score was used to compare symptoms before and after the intervention. Continuous variables were presented as means. Results: Among the 39 patients assessed, 27 met the inclusion criteria. Of these, 51% were male, with an average age of 48 years. The average lower esophageal sphincter pressure was 36 mmHg. The mean operative time and bleeding were 133 minutes and 34 mL, respectively. The average length of the myotomy was 8.3 cm. Partial fundoplication was performed in all cases, and intraoperative endoscopy was conducted in 88% of the cases. Two intraoperative mucosal perforations occurred. The average length of hospital stay was 2.7 days. There was one medical complication but no mortality. Dysphagia significantly improved by 95%, and the mean Eckardt score decreased from 7.7 to 1.2 after surgery (p < 0.001). The average follow-up period was 24 months. Conclusion: LHM with partial fundoplication proves to be an effective and safe procedure for treating achalasia. It results in the resolution of dysphagia in 95% of cases and carries minimal morbidity. Therefore, LHM should be considered the definitive treatment of choice for achalasia.

Introducción: la miotomía de Heller laparoscópica (MHL) se considera el tratamiento quirúrgico estándar en acalasia esofágica. A nivel local se desconocen las características clínicas de los pacientes y los resultados de la intervención. Metodología: estudio retrospectivo que incluye pacientes llevados a MHL durante un periodo de 8 años. Se analizaron variables demográficas, operatorias y posoperatorias. Mediante el puntaje de Eckardt se compararon síntomas antes y después de la intervención. Las variables continuas se expresan en promedios. Resultados: 27 de 39 pacientes cumplieron los criterios de inclusión. El 51% fueron hombres y el promedio de edad fue de 48 años. La presión promedio del esfínter esofágico inferior fue de 36 mm Hg. El promedio de tiempo operatorio y sangrado fue de 133 minutos y 34 mL, respectivamente. La longitud promedio de la miotomía fue de 8,3 cm. Se adicionó funduplicatura parcial en todos los casos y en el 88% se realizó una endoscopia intraoperatoria. Se presentaron 2 perforaciones intraoperatorias de la mucosa. El promedio de estancia hospitalaria fue 2,7 días. Hubo una complicación médica y ninguna mortalidad. La disfagia mejoró en el 95% y el promedio del puntaje de Eckardt disminuyó de 7,7 a 1,2 luego de cirugía (p < 0,001). El seguimiento fue de 24 meses en promedio. Conclusión: la MHL con funduplicatura parcial es un procedimiento efectivo y seguro para el tratamiento de la acalasia. Se asocia a resolución de la disfagia en el 95% de los casos, su morbilidad es mínima y debe considerarse el tratamiento definitivo de elección.

USP28 controls SREBP2 and the mevalonate pathway to drive tumour growth in squamous cancer.

SREBP2 is a master regulator of the mevalonate pathway (MVP), a biosynthetic process that drives the synthesis of dolichol, heme A, ubiquinone and cholesterol and also provides substrates for protein prenylation. Here, we identify SREBP2 as a novel substrate for USP28, a deubiquitinating enzyme that is frequently upregulated in squamous cancers. Our results show that silencing of USP28 reduces expression of MVP enzymes and lowers metabolic flux into this pathway. We also show that USP28 binds to mature SREBP2, leading to its deubiquitination and stabilisation. USP28 depletion rendered cancer cells highly sensitive to MVP inhibition by statins, which was rescued by the addition of geranyl-geranyl pyrophosphate. Analysis of human tissue microarrays revealed elevated expression of USP28, SREBP2 and MVP enzymes in lung squamous cell carcinoma (LSCC) compared to lung adenocarcinoma (LADC). Moreover, CRISPR/Cas-mediated deletion of SREBP2 selectively attenuated tumour growth in a KRas/p53/LKB1 mutant mouse model of lung cancer. Finally, we demonstrate that statins synergise with a dual USP28/25 inhibitor to reduce viability of SCC cells. Our findings suggest that combinatorial targeting of MVP and USP28 could be a therapeutic strategy for the treatment of squamous cell carcinomas.

Pronostico desfavorable de linfoma t/nk: reporte de casos / Unfavorable Prognosis of T/NK Lymphoma: Case Report

El linfoma de células T/NK tiene una frecuencia de presentación inusual, caracterizado por una progresión rápida y de mal pronóstico. Ocurrencia aludida a regiones de Asia y Latinoamérica por la fuerte incidencia de infección por el virus de Epstein- Barr. Su presentación puede ser nasal o en otra localización. Los esquemas de tratamiento suelen conllevar respuestas insuficientes, empero protocolos con base en L-Asparaginasa reflejarían mejores resultados. El presente reporte corresponde a 4 casos de este tipo de linfoma, 2 de tipo nasal y 2 de diversa presentación. Todos evolucionaron desfavorablemente, en parte por el mal pronóstico atribuido y también por el diagnóstico suscitado en etapas avanzadas de enfermedad concatenadas a dificultades económicas para sostener el tratamiento, factores intervinientes en nuestro medio.

NK/T cell lymphoma is an unusual neoplasm, characterized by fast progression and poor prognosis. It is present in regions of Asia and Latin America associated to a high incidence of Epstein-Barr virus infection. Its presentation can be nasal or in another location. Treatment schemes usually lead to insufficient responses, however protocols based on L-Asparaginase would reflect better results. This report concerns 4 cases of this lymphoma, 2 nasal type and 2 of a different presentation. Patients responses were unfavorable, partly due to the poor prognosis att r ibuted and also due to the diagnosis raised in advanced stages of the disease as well as to economic difficulties to sustain treatment, intervening factors in our country.

Long non-coding RNA PCAT19 safeguards DNA in quiescent endothelial cells by preventing uncontrolled phosphorylation of RPA2.

In healthy vessels, endothelial cells maintain a stable, differentiated, and growth-arrested phenotype for years. Upon injury, a rapid phenotypic switch facilitates proliferation to restore tissue perfusion. Here we report the identification of the endothelial cell-enriched long non-coding RNA (lncRNA) PCAT19, which contributes to the proliferative switch and acts as a safeguard for the endothelial genome. PCAT19 is enriched in confluent, quiescent endothelial cells and binds to the full replication protein A (RPA) complex in a DNA damage- and cell-cycle-related manner. Our results suggest that PCAT19 limits the phosphorylation of RPA2, primarily on the serine 33 (S33) residue, and thereby facilitates an appropriate DNA damage response while slowing cell cycle progression. Reduction in PCAT19 levels in response to either loss of cell contacts or knockdown promotes endothelial proliferation and angiogenesis. Collectively, PCAT19 acts as a dynamic guardian of the endothelial genome and facilitates rapid switching from quiescence to proliferation.

Participant experiences of intervention to detect and manage familial hypercholesterolaemia in Australian general practice: A qualitative descriptive study.

BACKGROUND AND OBJECTIVES: General practitioners (GPs) are ideally placed to have a much larger role in detection and management of familial hypercholesterolaemia (FH) among their patients. The aim of this study was to seek the reflections of practice staff and newly diagnosed patients with FH on the implementation of an FH model of care in the general practice setting. METHOD: Qualitative descriptive methodology was used. Interviews were conducted with 36 practice staff and 51 patients from 15 practices participating in the study. RESULTS: Data were analysed thematically and coded into themes - efficacy of GP training, screening for FH, model of care, patient awareness and cascade testing. DISCUSSION: Findings reflect the real-world clinical experience of Australian general practice and the acceptability of the model of care for both patients with FH and practice staff. Patient health literacy is a barrier to both management of FH and cascade testing. A systematic approach to cascade testing is required.

Skin sonography in children: a review.

Skin lesions are not uncommon in children, and most of them are benign. However, they can be a matter of concern. Although in most cases the diagnosis can be suspected based on clinical history and physical examination, in some cases clinical findings are nonspecific. High-frequency color Doppler US is a noninvasive technique that can play a relevant role in these cases and give important anatomical information for final clinical management. US can be helpful to avoid unnecessary surgery, plan a surgical excision and avoid advanced imaging studies such as MRI and CT, which have a lower resolution for the skin. Different lesions can look similar on US, and clinical correlation is always important. The purpose of this article is to show a variety of skin lesions that occur in children, emphasizing clinical-sonographic correlation, and to familiarize pediatric radiologists with the US technique and sonographic appearance of common skin lesions in children.

Cost impact of undertaking detection and management of familial hypercholesterolaemia in Australian general practice.

BACKGROUND AND OBJECTIVES: Familial hypercholesterolaemia (FH) can be effectively detected and managed in primary care, but the health economic evidence for this is scarce. The aim of this study was to examine management pathways and cost implications of FH screening and management in Australian general practice. METHOD: Cost-effectiveness outcomes were projected using a life table model. Data was used from 133 patients in 15 Australian general practice clinics from an earlier screening and management study. Costing and mortality data were sourced from governmental sources and published literature. RESULTS: Most patients had a regular general practice consultation at baseline (82%), though the proportion seen under a chronic disease management item at follow-up increased to 23%. The median cost of management was $275 per annum in the first year of management. Managing patients with statins up to the age of 60 years yielded an increase of 248,954 life-years at a cost of $759 million, representing a cost per life-year gained of $3047. DISCUSSION: Screening and management of FH in general practice has the potential for substantial health benefits while requiring relatively modest investments from the health system.

PTEN mutant non-small cell lung cancer require ATM to suppress pro-apoptotic signalling and evade radiotherapy.

BACKGROUND: Despite advances in treatment of patients with non-small cell lung cancer, carriers of certain genetic alterations are prone to failure. One such factor frequently mutated, is the tumor suppressor PTEN. These tumors are supposed to be more resistant to radiation, chemo- and immunotherapy. RESULTS: We demonstrate that loss of PTEN led to altered expression of transcriptional programs which directly regulate therapy resistance, resulting in establishment of radiation resistance. While PTEN-deficient tumor cells were not dependent on DNA-PK for IR resistance nor activated ATR during IR, they showed a significant dependence for the DNA damage kinase ATM. Pharmacologic inhibition of ATM, via KU-60019 and AZD1390 at non-toxic doses, restored and even synergized with IR in PTEN-deficient human and murine NSCLC cells as well in a multicellular organotypic ex vivo tumor model. CONCLUSION: PTEN tumors are addicted to ATM to detect and repair radiation induced DNA damage. This creates an exploitable bottleneck. At least in cellulo and ex vivo we show that low concentration of ATM inhibitor is able to synergise with IR to treat PTEN-deficient tumors in genetically well-defined IR resistant lung cancer models.

USP28 enables oncogenic transformation of respiratory cells, and its inhibition potentiates molecular therapy targeting mutant EGFR, BRAF and PI3K.

Oncogenic transformation of lung epithelial cells is a multistep process, frequently starting with the inactivation of tumour suppressors and subsequent development of activating mutations in proto-oncogenes, such as members of the PI3K or MAPK families. Cells undergoing transformation have to adjust to changes, including altered metabolic requirements. This is achieved, in part, by modulating the protein abundance of transcription factors. Here, we report that the ubiquitin carboxyl-terminal hydrolase 28 (USP28) enables oncogenic reprogramming by regulating the protein abundance of proto-oncogenes such as c-JUN, c-MYC, NOTCH and ∆NP63 at early stages of malignant transformation. USP28 levels are increased in cancer compared with in normal cells due to a feed-forward loop, driven by increased amounts of oncogenic transcription factors such as c-MYC and c-JUN. Irrespective of oncogenic driver, interference with USP28 abundance or activity suppresses growth and survival of transformed lung cells. Furthermore, inhibition of USP28 via a small-molecule inhibitor resets the proteome of transformed cells towards a 'premalignant' state, and its inhibition synergizes with clinically established compounds used to target EGFRL858R -, BRAFV600E - or PI3KH1047R -driven tumour cells. Targeting USP28 protein abundance at an early stage via inhibition of its activity is therefore a feasible strategy for the treatment of early-stage lung tumours, and the observed synergism with current standard-of-care inhibitors holds the potential for improved targeting of established tumours.

Estudio radiológico simple de quiste óseo simple y aneurismático: diagnóstico diferencial / Plain radiologic assessment of unicameral and aneurysmal bone cyst: differential diagnosis

OBJETIVO Dar a conocer nuestra experiencia en el diagnóstico diferencial de los quistes óseos simple y aneurismático mediante estudio radiológico simple. MATERIALES Y METODOS Se incluyeron pacientes menores de 20 años con radiografía de quiste óseo simple o aneurismático histológicamente confirmado pertenecientes al Registro Nacional de Tumores Óseos. Las radiografías fueron analizadas por dos radiólogos experimentados. Se compararon las variables demográficas de los pacientes, y las variables clínicas y radiológicas de ambos quistes. RESULTADOS Un total de 97 pacientes cumplieron los criterios de inclusión (65% presentaba quistes óseos simples y 35%, aneurismáticos). No se observaron diferencias en cuanto a la edad, al hueso comprometido, al tamaño de la lesión, a la expansión ósea, ni al adelgazamiento cortical. El género, la forma de presentación, la presencia de interrupción de la cortical, y la localización de la lesión en los ejes longitudinal y transversal del hueso son parámetros que podrían ser útiles en el diagnóstico diferencial de ambos quistes. DISCUSIÓN Los quistes óseos simple y aneurismático son lesiones benignas frecuentes que, de acuerdo con la literatura, serían difíciles de diferenciar únicamente con radiografía simple. La resonancia magnética permite una mejor caracterización anatómica, y aporta sensibilidad y especificidad al diagnóstico. Sin embargo, debe ser precedida por la radiografía simple, y su disponibilidad es limitada. CONCLUSIÓN Aun en centros con disponibilidad de resonancia magnética, la radiografía simple sigue siendo el estudio inicial de elección en el diagnóstico de tumores óseos. Ciertas características demográficas y radiográficas permiten orientar el diagnóstico diferencial inicial entre el quiste óseo simple y el aneurismático

OBJETIVE To describe our experience in the differential diagnosis of unicameral and aneurysmal bone cysts using plain radiography. PATIENCES AND METHODS We included patients under 20 years of age with radiographs of histologically-confirmed unicameral or aneurysmal bone cysts found on the Chilean National Bone-Tumor Registry. The radiographs were evaluated by two experienced radiologists. We compared the demographic variables of the patients, and the clinical and radiological variables of both tumors.. RESULTADOS A total of 97 patients met the inclusion criteria, 65% of whom had simple bone cysts, and 35%, aneurysmal bone cysts. No differences were found regarding age, the bone affected, the size of the lesion, bone expansion, nor cortical thinning. Gender, clinical presentation, cortical interruption, and location of the lesion on the longitudinal and transverse bone axes are parameters that could be used in the differential diagnosis of both cysts. DISCUSSION According to the literature, unicameral and aneurysmal bone cysts are frequent benign lesions that are difficult to differentiate merely through plain radiographs. Magnetic resonance imaging enables a better anatomical characterization and provides sensitivity and specificity to the diagnosis. However, its availability is limited, and it should be preceded by plain radiography. CONCLUSION Plain radiography is still the initial imaging study of choice in patients with clinical suspicion of bone tumor, even in those centers where magnetic resonance imaging is available. Certain demographic and radiological characteristics guide physicians in the differential diagnosis of unicameral and aneurysmal bone cysts.

Infantile/Capillary Hemangioma of the Uterine Corpus: A Rare Cause of Abnormal Genital Bleeding.

BACKGROUND: Infantile hemangiomas are vascular anomalies. However, they rarely cause genital bleeding. Here, we present the case of a young female with an endocavitary hemangioma who presented with abnormal uterine bleeding (AUB). CASE: The patient was an 8-year-old female with genital bleeding. Transabdominal pelvic ultrasound showed a 20-mm highly vascularized focal intrauterine endocavitary lesion. Vascular computerized tomography excluded vascular anomalies. Magnetic resonance imaging suggested a hemangioma. Minimally invasive open surgery was performed to remove the lesion. Subsequent pathology analyses confirmed an infantile/capillary hemangioma. CONCLUSIONS: Infantile hemangiomas are vascular anomalies that should be considered potential causes of AUB in early puberty. The study of these cases should include pelvic ultrasound and vascular magnetic resonance imaging. Experienced surgeons can successfully accomplish fertility-sparing surgical procedures. SUMMARY: We describe an unusual case of peripubertal AUB caused by an endocavitary capillary hemangioma. Management included fertility-sparing surgery and the complete resolution of symptoms.

Inhibition of USP28 overcomes Cisplatin-resistance of squamous tumors by suppression of the Fanconi anemia pathway.

Squamous cell carcinomas (SCC) frequently have an exceptionally high mutational burden. As consequence, they rapidly develop resistance to platinum-based chemotherapy and overall survival is limited. Novel therapeutic strategies are therefore urgently required. SCC express ∆Np63, which regulates the Fanconi Anemia (FA) DNA-damage response in cancer cells, thereby contributing to chemotherapy-resistance. Here we report that the deubiquitylase USP28 is recruited to sites of DNA damage in cisplatin-treated cells. ATR phosphorylates USP28 and increases its enzymatic activity. This phosphorylation event is required to positively regulate the DNA damage repair in SCC by stabilizing ∆Np63. Knock-down or inhibition of USP28 by a specific inhibitor weakens the ability of SCC to cope with DNA damage during platin-based chemotherapy. Hence, our study presents a novel mechanism by which ∆Np63 expressing SCC can be targeted to overcome chemotherapy resistance. Limited treatment options and low response rates to chemotherapy are particularly common in patients with squamous cancer. The SCC specific transcription factor ∆Np63 enhances the expression of Fanconi Anemia genes, thereby contributing to recombinational DNA repair and Cisplatin resistance. Targeting the USP28-∆Np63 axis in SCC tones down this DNA damage response pathways, thereby sensitizing SCC cells to cisplatin treatment.

Infecciones abdominales por Actinomyces odontolyticus: comunicación de dos casos / Abdominal infections due Actinomyces odontolyticus: a report of two cases

Resumen Actinomyces spp es una familia de bacilos grampositivos saprofíticos que rara vez producen infecciones en el ser humano. Actinomyces odontolyticus forma parte de la microbiota oral y existen escasos reportes de casos de infecciones asociadas a este microorganismo, principalmente de localización oral, torácica, pélvica y bacteremias. Estas infecciones se caracterizan por ser recidivantes y causar abscesos y trayectos fistulosos. Su aislamiento microbiológico es difícil ya que la mayoría de los equipos automatizados no identifican la especie de Actinomyces, por lo que técnicas como MALDI-TOF MS resulta de gran ayuda en el diagnóstico definitivo. Finalmente, el tratamiento antibacteriano debe ser prolongado, acompañado del drenaje quirúrgico de las colecciones. Presentamos dos casos de infección abdominal recurrente por A. odontolyticus, en pacientes inmunocompetentes, con tratamiento exitoso.

Abstract Actinomyces spp is a family of saprophytic gram-positive rods that rarely cause infections in humans. Actinomyces odontolyticus is part of the oral microbiota and there are few case reports of infections associated, mainly oral, thoracic, pelvic involvement and bacteremia. These infections are characterized by being recurrent and causing abscesses and fistulous tracts. Microbiological isolation of the microorganism is difficult because most of the automated identification equipment does not detect the Actinomyces species. The use of identification techniques such as MALDI-TOF MS is a great help in the definitive diagnosis. Finally, antibacterial treatment should be prolonged, and accompanied by surgical drainage of the collections. We report two cases of recurrent abdominal infection by A. odontolyticus, in immunocompetent patients, with successful treatment.

USP28: Oncogene or Tumor Suppressor? A Unifying Paradigm for Squamous Cell Carcinoma.

Squamous cell carcinomas are therapeutically challenging tumor entities. Low response rates to radiotherapy and chemotherapy are commonly observed in squamous patients and, accordingly, the mortality rate is relatively high compared to other tumor entities. Recently, targeting USP28 has been emerged as a potential alternative to improve the therapeutic response and clinical outcomes of squamous patients. USP28 is a catalytically active deubiquitinase that governs a plethora of biological processes, including cellular proliferation, DNA damage repair, apoptosis and oncogenesis. In squamous cell carcinoma, USP28 is strongly expressed and stabilizes the essential squamous transcription factor ΔNp63, together with important oncogenic factors, such as NOTCH1, c-MYC and c-JUN. It is presumed that USP28 is an oncoprotein; however, recent data suggest that the deubiquitinase also has an antineoplastic effect regulating important tumor suppressor proteins, such as p53 and CHK2. In this review, we discuss: (1) The emerging role of USP28 in cancer. (2) The complexity and mutational landscape of squamous tumors. (3) The genetic alterations and cellular pathways that determine the function of USP28 in squamous cancer. (4) The development and current state of novel USP28 inhibitors.