Large-scale genomic analyses with machine learning uncover predictive patterns associated with fungal phytopathogenic lifestyles and traits.

Invasive plant pathogenic fungi have a global impact, with devastating economic and environmental effects on crops and forests. Biosurveillance, a critical component of threat mitigation, requires risk prediction based on fungal lifestyles and traits. Recent studies have revealed distinct genomic patterns associated with specific groups of plant pathogenic fungi. We sought to establish whether these phytopathogenic genomic patterns hold across diverse taxonomic and ecological groups from the Ascomycota and Basidiomycota, and furthermore, if those patterns can be used in a predictive capacity for biosurveillance. Using a supervised machine learning approach that integrates phylogenetic and genomic data, we analyzed 387 fungal genomes to test a proof-of-concept for the use of genomic signatures in predicting fungal phytopathogenic lifestyles and traits during biosurveillance activities. Our machine learning feature sets were derived from genome annotation data of carbohydrate-active enzymes (CAZymes), peptidases, secondary metabolite clusters (SMCs), transporters, and transcription factors. We found that machine learning could successfully predict fungal lifestyles and traits across taxonomic groups, with the best predictive performance coming from feature sets comprising CAZyme, peptidase, and SMC data. While phylogeny was an important component in most predictions, the inclusion of genomic data improved prediction performance for every lifestyle and trait tested. Plant pathogenicity was one of the best-predicted traits, showing the promise of predictive genomics for biosurveillance applications. Furthermore, our machine learning approach revealed expansions in the number of genes from specific CAZyme and peptidase families in the genomes of plant pathogens compared to non-phytopathogenic genomes (saprotrophs, endo- and ectomycorrhizal fungi). Such genomic feature profiles give insight into the evolution of fungal phytopathogenicity and could be useful to predict the risks of unknown fungi in future biosurveillance activities.

Inhibition of casein kinase 2 sensitizes mantle cell lymphoma to venetoclax through MCL-1 downregulation.

BCL-2 family proteins are frequently aberrantly expressed in mantle cell lymphoma (MCL). Recently, the BCL-2-specific inhibitor venetoclax has been approved by the US Food and Drug Administration for chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML). In MCL, venetoclax has shown promising efficacy in early clinical trials; however, a significant subset of patients is resistant. By conducting a kinome-centered CRISPR-Cas9 knockout sensitizer screen, we identified casein kinase 2 (CK2) as a major regulator of venetoclax resistance in MCL. Interestingly, CK2 is over-expressed in MCL and high CK2 expression is associated with poor patient survival. Targeting of CK2, either by inducible short hairpin RNA (shRNA)-mediated knockdown of CK2 or by the CK2-inhibitor silmitasertib, did not affect cell viability by itself, but strongly synergized with venetoclax in both MCL cell lines and primary samples, also if combined with ibrutinib. Furthermore, targeting of CK2 reduced MCL-1 levels, which involved impaired MCL-1 translation by inhibition of eIF4F complex assembly, without affecting BCL-2 and BCL-XL expression. Combined, this results in enhanced BCL-2 dependence and, consequently, venetoclax sensitization. In cocultures, targeting of CK2 overcame stroma-mediated venetoclax resistance of MCL cells. Taken together, our findings indicate that targeting of CK2 sensitizes MCL cells to venetoclax through downregulation of MCL-1. These novel insights provide a strong rationale for combining venetoclax with CK2 inhibition as therapeutic strategy for MCL patients.

An Unbiased CRISPR-Cas9 Screening Method for the Identification of Positive and Negative Regulatory Proteins of Cell Adhesion.

Mature B-cell lymphomas are highly dependent upon the protective lymphoid organ microenvironment for their growth and survival. Targeting integrin-mediated homing and retention of the malignant B cells in the lymphoid organs, using the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, is a highly efficacious FDA-approved therapy for chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), and Waldenström macroglobulinemia (WM). Unfortunately, a significant subset of patients is intrinsically resistant to ibrutinib or will develop resistance upon prolonged treatment. Here, we describe an unbiased functional genomic CRISPR-Cas9 screening method to identify novel proteins involved in B-cell receptor-controlled integrin-mediated adhesion, which provides novel therapeutic targets to overcome ibrutinib resistance. This screening method is highly flexible and can be easily adapted to identify cell adhesion-regulatory proteins and signaling pathways for other stimuli, adhesion molecules, and cell types. Graphical abstract.

A loss-of-adhesion CRISPR-Cas9 screening platform to identify cell adhesion-regulatory proteins and signaling pathways.

The clinical introduction of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib, which targets B-cell antigen-receptor (BCR)-controlled integrin-mediated retention of malignant B cells in their growth-supportive lymphoid organ microenvironment, provided a major breakthrough in lymphoma and leukemia treatment. Unfortunately, a significant subset of patients is intrinsically resistant or acquires resistance against ibrutinib. Here, to discover novel therapeutic targets, we present an unbiased loss-of-adhesion CRISPR-Cas9 knockout screening method to identify proteins involved in BCR-controlled integrin-mediated adhesion. Illustrating the validity of our approach, several kinases with an established role in BCR-controlled adhesion, including BTK and PI3K, both targets for clinically applied inhibitors, are among the top hits of our screen. We anticipate that pharmacological inhibitors of the identified targets, e.g. PAK2 and PTK2B/PYK2, may have great clinical potential as therapy for lymphoma and leukemia patients. Furthermore, this screening platform is highly flexible and can be easily adapted to identify cell adhesion-regulatory proteins and signaling pathways for other stimuli, adhesion molecules, and cell types.

Flexible ureteroscopy in extreme elderly patients (80 years of age and older) is feasible and safe.

PURPOSE: To compare the safety and efficacy of RIRS in patients ≥ 80 years to a younger population. METHODS: We retrospectively compared the data from patients ≥ 80 years of age undergoing RIRS with the data of a group of patients from 18 and < 80 years. Perioperative outcomes, complications and emergency department visits were compared between two groups. RESULTS: A total of 173 patients were included in the study. Mean age was 44 (27-79) and 81 years-old (80-94), for younger and elderly group, respectively. Elderly patients had higher ASA scores (≥ 3) (28.6% vs 75.8%; p = 0.0001) and Charlson comorbidity index (1.99 vs 7.86; p = 0.0001), more diabetes (p = 0.006) and respiratory comorbidities (p = 0.002). No statistical difference was found between two groups in stone size (p = 0.614) and number (p = 0.152). Operative time (74.48 vs 102.96 min; p = 0.0001) and duration of hospitalisation (1.7 vs 2.9 days; p = 0.001) were longer for the elderly. Intraoperative complication rate did not show differences between the two groups (p = 0.166). Postoperative complications rates were similar between the cohorts (7.7% vs 9.5%; p = 0.682). The success rates were 67.5% in the younger group and 71.4% in the elderly group (p = 0.584). No difference was seen in stone recurrence (p = 0.73). A higher rate of visits to the emergency department was found in younger cohort (23.6% vs 11.6%; p = 0.046), mostly duo to stent-related symptoms. CONCLUSIONS: Despite the higher rate of comorbidity in the elderly group, RIRS was a safe procedure with similar complication rate and outcomes at an expense of higher operative time and hospital stay.

Fragmentation targeted at preferred discontinuities: A new concept in endolithotripsy with Holmium laser:YAG. / Fragmentación dirigida a discontinuidades preferentes: un nuevo concepto en endolitotricia con láser Holmium:YAG.

INTRODUCTION: There are currently 3holmium laser, YAG (Ho:YAG) endolithotripsy procedures that are considered basic (fragmentation, pulverisation, "pop-corn" technique). We present the technique of fragmentation targeted at preferred discontinuities (FTPD), a new concept of endolithotripsy by Ho:YAG laser. MATERIAL AND METHODS: The FTPD technique is based on the selective application of energy (targeting a specific preselected point) to an area that is visually prone to the formation of a fracture line or preferred discontinuity (conditioned by the anisotropy of the urolithiasis). The ideal energy regimen (setting) is a high range of working energy (2-3J) with a very low frequency range (5-8Hz) and short pulse width. Between January 2015 to February 2017, the FTPD technique was used in 37 procedures (7 NLP, 16 RIRS, 12 URS, 2 cystolithotomies), with a Ho:YAG laser (Lumenis Pulse 120H®, Tel-Aviv, Israel). Maximum power used: 24W (3J/8Hz) with fibres of 365µ and 273µ (URS, RIRS), and 32W (4J/8Hz) with fibres of 550µ (NLP, cystolithotomy). RESULTS: Strategic improvement was achieved in all cases using the TFPD technique to continue the endolithotripsy or remove fragments. No complications were recorded after the use of this method. CONCLUSIONS: FTPD can be considered a complementary option in combination with the basic methods of fragmentation and pulverisation. In our experience, it constitutes significant progress in optimising the performance of Ho:YAG laser endolithotripsy.

Corinebacterium urealyticum: increased incidence of infection and encrusted uropathy.

INTRODUCTION: Corynebacterium urealyticum (CU) affects patients who are immunosuppressed, chronically ill or have undergone numerous operations. Obstructive uropathy (OU) is a complication of infection. STUDY OBJECTIVE: To demonstrate the growing increase in cases of infection by CU and OU in the past 5 years. MATERIAL AND METHODS: A descriptive study was conducted of urological patients with CU-positive urine cultures (January 2009-December 2014). We calculated the annual distribution and clinical characteristics of infection by CU and OU. Minimum follow-up: 6 months. We obtained the statistical means and ranges of clinical parameters pre/post-therapy. RESULTS: The total number of patients with CU was 115 (men, 87; women, 28). The mean age was 67.9 years (range, 6-95 years), and the annual distribution of cases for 2009, 2010, 2011, 2012, 2013 and 2014 was 9 (7.8%), 13 (11.3%), 9 (7.8%), 20 (17.4%), 31 (27%) and 33 (28.7%), respectively. The increase in cases for 2009-2014 was 300%. Multiple urological surgeries were performed in 89 cases (77.3%), with surgical complications in 77 cases (66.9%). Eighteen (15.6%) patients had OU (men, 13; women, 5), 12 had pyelitis (66.7%), 3 had cystopathy (16.6%), 2 had prostatic capsule disease (11.2%) and 1 had mesh calcification (5.5%). The analysis of the 18 cases with OU showed pre/postantibiotic therapy urine pHs of 8 (r, 6-9) vs. 6 (r, 5-7). All postantibiotic cultures were negative. Acidifying solution was applied in 5 cases, and surgery was performed in 13 cases (72.2%). The results from before/after the multimodal therapy showed renal impairment in 12 (66.6%) vs. 9 cases (50%) and glomerular filtration rates (GFR) of 45.8 (r, 6->90) vs. 52.7 (r, 13->90). The improvement in GFR was 6.94 points (T Wilcoxon; P=.102). The radiology results (incrustations) showed improvement in 13 patients (72.2%) and no change in 5 (27.8%). There was no specific mortality for CU. CONCLUSIONS: The prevalence of infection by CU and OU is increasing. Antibiotic treatment is highly effective. Acidifying solutions are an acceptable option for reducing calcifications.

Uropatía incrustante por Corynebacterium urealiticum: comentarios a partir de tres casos clínicos / Fouling uropathy by Corynebacterium urealyticum: Comments from three clinical cases

La uropatía incrustante es una enfermedad infecciosa del tracto urinario causada por la bacteria urealítica Corynebacterium urealyticum (CU). En nuestra serie (datos no publicados) sólo el 15% de las infecciones por CU produce uropatía incrustante. La formación de incrustaciones de estruvita y apatita en la pared del urotelio puede afectar a pelvis renal (pielitis), uréter, vejiga (cistopatía) y próstata, incluyendo la celda prostática después de resección ("celdopatía"). La pielitis es la más frecuente. La clínica corresponde a la triada orina alcalina, piuria y cristaluria de estruvita. Los pacientes suelen ser inmunodeprimidos o multioperados. El cultivo de orina debe estar dirigido al diagnóstico de CU. La TC es la prueba de imagen de elección. Muestra típicas imágenes de calcificación laminar. El tratamiento de la uropatía incrustante es multimodal. Incluye antibioterapia, acidificación de la orina y cirugía (algunos casos) (AU)

The encrustant uropathy is an infectious disease of the urinary tract caused by urealithic bacteria Corynebacterium urealyticum (CU). In our series (unpublished data) only 15% of CU infections caused encrustant uropathy. Formation of apatite and struvite on the wall of the urothelium can affect renal pelvis (pyelitis), urether, bladder (cystophatie) and prostate, including prostate cell after resection ("cellpathy"). Pyelitis is the most common. Clinical triad corresponds to alkaline urine, pyuria and struvite crystalluria. Patients are usually immunocompromised or or multiple previous surgeries. Urine culture should be directed to the diagnosis of UC. CT is the imaging test of choice. Shows typical images of laminar calcification. Treatment of encrusted uro pathy is multimodal. Includes antibiotics, acidification of urine and surgery (sometimes) (AU)

Hemangioma papilar como causa de macrohematuria. Presentación de un caso y revisión de la literatura / Papillary hemangioma as a cause of macrohematuria. A case report and review of the literature

La hematuria recidivante unilateral supone un reto diagnóstico y terapéutico para el urólogo. El hemangioma renal (HR) figura entre las posibles causas. La localización en la papila renal es típica. Se presenta un caso de hematuria secundaria a HR que fue diagnosticado en primera instancia como síndrome del cascanueces. Tras una revaloración se realizó ureterorrenoscopia que demostró un hemangioma papilar sangrante. La lesión fue tratada con fotovaporización láser con buen resultado. Se revisa la etiopatogenia, diagnóstico y las opciones terapéuticas frente al HR sangrante (AU)

Unilateral recurrent hematuria is a diagnostic and therapeutic challenge for the urologist. The renal hemangioma (RH) is a possible cause. The location is typically the renal papilla. A case of hematuria secondary to RH who was diagnosed at first instance and nutcracker syndrome is presented. After a diagnostic reassessment ureterorenoscopy was performed which showed a bleeding papillary hemangioma. The lesion was treated with laser PVP with good results. The pathogenesis, diagnosis and therapeutic options against the bloody RH is reviewed (AU)

Implications of vitamin D deficiency in lithiasic patient and in general population.

CONTEXT AND OBJECTIVE: Vitamin D deficiency causes problems in mineral metabolism but also overall health. In first place a review of the topic was carried out. Then, in order to contextualize it in lithiasic patient, a study on Vitamin D deficiency and its possible relationship with impaired PTH levels is performed. EVIDENCES ACQUISITION: A review of topics such as metabolism, epidemiology and the relationship of vitamin D deficiency with several pathologies was performed. Besides a multivariate analysis and a correlation study between vitamin D and PTH levels was conducted in 100 lithiasic patients. EVIDENCES SYNTHESIS: We present a review of Vitamin D metabolism, receptors and functions, as well as about its valuation methodology and the treatment of its deficiency. Lithiasic patients show a higher vitamin D deficiency than general population. Vitamin D deficiency has been significantly associated with increased PTH levels. In addition, there is enough literature showing a relationship between vitamin D deficiency not only with bone disease, but also with multiple diseases. CONCLUSION: vitamin D levels should be measured in all lithiasic patients, and those with vitamin D deficiency should be treated.

Infecciones de transmisión sexual en el varón: actitud práctica diagnóstico-terapéutica / STDs in men: diagnostic-therapeutic practical attitude

Las infecciones de transmisión sexual (ITS) son un grupo de enfermedades que afectan a la población que mantiene actividad sexual. Su distribución es muy amplia y afecta a ambos géneros. Para las uretritis por clamidia, ureaplasma y gonococo se utilizan cada vez más las pruebas de ampliación genómica como el test de reacción en cadena de la polimerasa (PCR). La balanitis por gardnerella y candida se diagnostican con cultivo de secreción y se tratan con terapia médica. Para el diagnóstico de la sifilis siguen en vigor las pruebas (reagínicas) como VDRL y las RPR y las treponémicas (no reagínicas) como FTA y TPHA. El tratamiento de todas ellas es antibiótico e incluye a las parejas. El herpes simple (VHS) se diagnostica clínicamente. La serología confirma el diagnóstico. El tratamiento con antivirales mejora el pronóstico. El virus del papiloma humano (VPH) se trata con eliminación química o física de las lesiones. El molusco contagioso se extirpa mecánicamente. En este trabajo se revisa el diagnóstico y el tratamiento práctico de las principales ITS que afectan al género masculino (AU)

Sexually Transmitted Infections (STIs) are a group of diseases affecting population that keeps sexual activity. Their distribution is very wide and affects both sexes. For urethritis chlamydia, ureaplasma and gonococcus genomic tests enlargement as test chain reaction (PCR) are used increasingly. The gardnerela and candida balanitis are diagnosed with secretion culture and treated with medical therapy. For the diagnosis of syphilis remain in reaginic and no reaginic tests). Treatment of these is antibiotic and includes couples. Herpes simplex virus (HSV) is diagnosed clinically. Serology confirms the diagnosis. Antiviral treatment improves prognosis. The Human Papilloma Virus (HPV) is treated with chemical or physical removal of the lesions. Molluscum contagiosum is removed mechanically. In this paper practical diagnosis and treatment of major ITS affecting male is reviewed (AU)

Litiasis úrica coraliforme bilateral de origen intestinal. Presentación de un caso tratado con la combinación quirúrgica NLP/RIRS/ECIRS / Uric bilateral staghorn lithiasis of intestinal origin. Report of a case treated with surgical combination NLP / RIRS / ECIRS

La cirugía endoscópica renal (por vía percutánea o por vía retrograda) se ha consolidado como una técnica de elección para los cálculos renales. En los más voluminosos (mayores de 2-3 cm de diámetro mayor) está indicada la nefrolitotomía percutánea (NLP) y en los menores la cirugía retrógrada intrarrenal RIRS (exceptuando los tratables con litotricia extracorpórea por ondas de choque). La ECIRS es una modalidad mixta. La litotricia endoscópica con láser es un tratamiento eficaz en las tres técnicas. En NLP es necesario usar altas energías La litiasis de AU representan un 10% del total de cálculos en España. Entre los factores etiológicosfiguran la dieta, los procesos inductores de lisis celular (ciertas neoplasias, quimioterapia) y algunos trastornos digestivos. Aunque la bilateralidad es muy frecuente es más raro encontrar coraliformes bilaterales. Presentamos un caso de litiasis renal úrica bilateral coraliforme (AU)

Renal endoscopic surgery (percutaneously or via retrograde) has become a technique of choice for kidney stones. In the more bulky (greater than 2-3 cm in diameter) is indicated percutaneous nephrolithotomy (PCNL). In smaller is indicated intrarenal retrograde surgery (RIRS), excluding those that can be treated with extracorporeal shock wave lithotripsy. The ECIRS is a mixed mode. Endoscopic laser lithotripsy is an effective treatment in the three techniques. In NLP is necessary to use high energy. The uric acid stones account for 10% of all stones in Spain. Etiologic factors include diet, conditions inducing cell lysis (certain malignancies, chemotherapy) and some digestive disorders. Although it is very frequent bilaterality is rare to find bilateral staghorn. We report a case of bilateral staghorn uric kidney stones secondary to intestinal disorder treated with a combination of three pocedures (AU)

Pólipo ureteral fibroepitelial. Revisión de la literatura / Fibroepithelial ureteral polyp. Review of the literature

Los pólipos fibroepiteliales (PF) del uréter son poco frecuentes para plantear un serio problema de diagnóstico diferencial con el carcinoma urotelial. Entre ambos existen algunas diferencias radiológicas pero no siempre es fácil reconocerlas. Históricamente, se ha realizado nefroureterectomia innecesariamente en muchos casos de pólipos. Con el avance de la instrumentación, la ureterorrenoscopia es una prueba de gran utilidad para el diagnóstico de los defectos de repleción ureteral. La biopsia confirma el diagnóstico. Los PF que provocan obstrucción del tracto urinario superior precisan de tratamiento endourológico o laparoscópico (AU)

Fibroepithelial polyps (FP) of the ureter are infrequent benign tumors often not easily distinguished from malignant transitional-cell carcinomas by radiologic means. Historically, many patients have undergone unnecessary nephroureterectomy for these lesions. With the advancement in endourologic instrumentation, the ureteroscopy is the gold standard of diagnosis for ureteral filling defect. When FP causes upper urinary tract obstruction can be treated with endourology or laparosocopy (AU)

Versión española del cuestionario USSQ: evaluación de la tolerancia clínica al catéter ureteral doble jota / Spanish version of the USSQ questionnaire: evaluation of clinical tolerance to double J uretheral catheter

INTRODUCCIÓN: La evaluación de los síntomas debidos a catéter ureteral doble jota (CUJJ) precisa de una herramienta fiable como el cuestionario USSQ. Se presenta una versión traducida al español de este cuestionario (USSQ-E). MATERIAL Y MÉTODOS: La versión en inglés del USSQ ha sido traducida al español siguiendo una sofisticada sistemática lingüística. Una vez obtenido el USSQ-E ha sido probado en un grupo de 70 pacientes portadores de CUJJ. Como grupo control se han tomado 40 personas sin catéter. RESULTADOS: Se ha evaluado el USSQ-E con pruebas de consistencia interna, test-retest, validez convergente, sensibilidad al cambio y validez discriminatoria, siendo todas ellas satisfactorias. CONCLUSIÓN: El USSQ-E es una herramienta válida y fiable para evaluar la sintomatología derivada del CUJJ en población hispanoparlante (AU)

INTRODUCTION: The assessment of symptoms due to double J ureteral catheter (CUJJ) requires a reliable tool like USSQ questionnaire. A translation in Spanish of this questionnaire (USSQ-E) version is presented. MATERIAL AND METHODS: The English version of USSQ has been translated into Spanish language following a systematic sophisticated. After obtaining the USSQ-E has been tested in a group of 70 patients with CUJJ. A control group of 40 people have been taken without catheter. RESULTS: We evaluated the USSQ-E with evidence of internal consistency, test-retest reliability, convergent validity, sensitivity to change and discriminant validity, all of which are satisfactory. CONCLUSION: USSQ-E is a valid and reliable for assessing symptomatology derived CUJJ tool in speaking population (AU)