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Abstract The human silencing hub (HUSH) complex binds to transcripts of LINE-1 retrotransposons (L1s) and other genomic repeats, recruiting MORC2 and other effectors to remodel chromatin. How HUSH and MORC2 operate alongside DNA methylation, a central epigenetic regulator of repeat transcription, remains largely unknown. Here we interrogate this relationship in human neural progenitor cells (hNPCs), a somatic model of brain development that tolerates removal of DNA methyltransferase DNMT1. Upon loss of MORC2 or HUSH subunit TASOR in hNPCs, L1s remain silenced by robust promoter methylation. However, genome demethylation and activation of evolutionarily-young L1s attracts MORC2 binding, and simultaneous depletion of DNMT1 and MORC2 causes massive accumulation of L1 transcripts. We identify the same mechanistic hierarchy at pericentromeric α-satellites and clustered protocadherin genes, repetitive elements important for chromosome structure and neurodevelopment respectively. Our data delineate the epigenetic control of repeats in somatic cells, with implications for understanding the vital functions of HUSH-MORC2 in hypomethylated contexts throughout human development.

Summary: Traumatic brain injury (TBI) is a leading cause of chronic brain impairment and results in a robust, but poorly understood, neuroinflammatory response that contributes to the long-term pathology. We used single-nuclei RNA sequencing (snRNA-seq) to study transcriptomic changes in different cell populations in human brain tissue obtained acutely after severe, life-threatening TBI. This revealed a unique transcriptional response in oligodendrocyte precursors and mature oligodendrocytes, including the activation of a robust innate immune response, indicating an important role for oligodendroglia in the initiation of neuroinflammation. The activation of an innate immune response correlated with transcriptional upregulation of endogenous retroviruses in oligodendroglia. This observation was causally linked in vitro using human glial progenitors, implicating these ancient viral sequences in human neuroinflammation. In summary, this work provides insight into the initiating events of the neuroinflammatory response in TBI, which has therapeutic implications.

Villous adenoma is a benign neoplasm with an exceptional presentation in the renal pelvis, hence very few cases have been reported. Herein we present the case of a patient who presented with left flank pain clinically suggestive of complicated pyelonephritis, culminating in simple nephrectomy with a villous adenoma in the renal pelvis as histopathological finding associated to the presence of a microscopic focus of intestinal-type adenocarcinoma.

Abstract Background Adiponectin gene (ADIPOQ) polymorphisms have been shown to affect adiponectin serum concentration and some have been associated with breast cancer (BC) risk. The aims of this study were to describe the frequency of single nucleotide polymorphisms (SNPs) of ADIPOQ in Mexican women with BC and to determine if they show an association with it. Methods DNA samples from 397 patients and 355 controls were tested for the ADIPOQ gene SNPs: rs2241766 (GT) and rs1501299 (GT) by TaqMan allelic discrimination assay. Hardy–Weinberg equilibrium (HWE) was tested. Multiple SNP inheritance models adjusted by age and body mass index (BMI) were examined for the SNP rs1501299. Results We found that in the frequency analysis of rs1501299 without adjusting the BMI and age, the genotype distribution had a statistically significant difference (P = 0.003). The T allele was associated with a BC risk (OR, 1.99; 95% CI 1.13–3.51, TT vs. GG; OR, 1.53; 95% CI 1.12–2.09, GT vs. GG). The SNP rs2241766 was in HW disequilibrium in controls. In conclusion, the rs1501299 polymorphism is associated with a BC risk. Conclusions Identification of the genotype of these polymorphisms in patients with BC can contribute to integrate the risk profile in both patients and their relatives as part of a comprehensive approach and increasingly more personalized medicine.

Collision tumors (CT) refer to the phenomenon where two or more apparently different and unrelated tumors occur within the same location in an organ, forming the same lesion. We present the first case of renal CT with a mixed component of clear cell carcinoma and collecting duct carcinoma (CDC) with rhabdoid and sarcomatoid characteristics treated with the combination of cabozantinib and nivolumab. A 47-year-old man arrived at our clinic referring persistent dry cough, accompanied by a weight loss of 12 kg in the previous two months. Imaging studies revealed bilateral pulmonary lesions of metastatic appearance associated with a large tumor in the left kidney. After radical nephrectomy the histopathological report revealed a renal cell carcinoma (collecting duct carcinoma 85% and clear cell carcinoma 15%). The patient was included in a treatment protocol based on cabozantinib 40 mg QD plus nivolumab 240 mg every 15 days, obtaining a partial response after two months. This response was maintained for 12 months after initiation of systemic treatment. This is the first documented case of renal CT with a CDC component that obtained a partial response to combined treatment with immunotherapy and target therapy as first-line treatment; obtaining the longest overall survival reported in the setting of a metastatic renal CT with this histological combination. We need to expand the knowledge regarding the treatment of metastatic CDC, either as a single entity or as a component of a renal CT, in order to offer the best possible therapeutic outcome.

Bilateral testicular germ cell tumors (BTGCT) occur in 1 to 4% of patients with testicular cancer and of these, 10-15% are synchronous. Overall, BTGCT represents less than 0.5% of all new cases of testicular cancer. There are few reports in the literature of synchronous BTGCT with different histology. We present the case of a 30-year-old man who presented to our genitourinary tumor unit with a bilateral increase of testicular volume. After initial assessment, a testicular ultrasound showed the presence of solid tumors in both testes. Staging studies were negative for metastatic disease. The patient was referred to the fertility clinic for sperm banking and later underwent a bilateral radical orchiectomy. The histopathology evaluation revealed a 5.5 cm right-sided mixed germ cell tumor and a 1.5 cm left-sided testicular seminoma. Because patient´s poor compliance for surveillance was identified as a risk factor for relapse and poor outcome, adjuvant chemotherapy was favored. The patient underwent one cycle of bleomycin, etoposide and cisplatin (BEP). After four years of follow up, the patient shows no evidence of relapse, either clinically or radiologically. In men unlikely to carry out successful surveillance; active treatment is the preferred option for preventing disease recurrence, even in patients with no risk factors. The physician must consider all available therapeutic measures in this scenario to achieve the best possible therapeutic result.

Tumors of the paratesticular region are generally tumors of slow growth, with little symptomatology and, in most cases, benign in nature; in this area, a borderline serous tumor may arise hypothetically from Müllerian metaplasia of the tunica vaginalis, which is histologically identical to its ovarian counterpart. We present a 10-year-old male, with right gynecomastia and ipsilateral hydrocele, showing an enlarged right testicle with a volume of 12 ml and a left testicle with a volume of 10 ml. A right orchiectomy was performed, which presented a poorly defined tan tumor of 1.8 cm that occupied the vaginal and epididymal tunica, and infiltrates the testicular parenchyma. Histological sections revealed a cystic neoplasm, with hierarchical papillary projections, covered by one or several epithelial columnar and hobnail cells with moderate atypia and scant mitosis. Immunohistochemical reactions were performed, resulting positive for PAX-8, epithelial membrane antigen, and CK7, confirming the diagnosis of borderline serous tumor. Since the first reported case in 1986, few have been reported, the majority of these in adults with only three cases in children. In the few cases reported, the prognosis is usually favorable after surgical resection, with disease-free follow-up for up to 18 years.

Abstract Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer tumors. Comparisons between TNBC and non-triple-negative breast cancer (nTNBC) may help to differentiate key components involved in TNBC neoplasms. The purpose of the study was to analyze the expression profile of TNBC versus nTNBC tumors in a homogeneous population from northeastern Mexico. A prospective study of 50 patients (25 TNBC and 25 nTNBC) was conducted. Clinic parameters were equally distributed for TNBC and nTNBC: age at diagnosis (51 versus 47 years, p = 0.1), glucose level (107 mg/dl versus 104 mg/dl, p = 0.64), and body mass index (28 versus 29, p = 0.14). Core biopsies were collected for histopathological diagnosis and gene expression analysis. Total RNA was isolated and expression profiling was performed. Forty genes showed differential expression pattern in TNBC tumors. Among these, nine overexpressed genes (PRKX/PRKY, UGT8, HMGA1, LPIN1, HAPLN3, FAM171A1, BCL141A, FOXC1, and ANKRD11), and one underexpressed gene (ANX9) are involved in general metabolism. Based on this biochemical peculiarity and the overexpression of BCL11A and FOXC1 (involved in tumor growth and metastasis, respectively), we validated by quantitative polymerase chain reaction the expression profiles of seven genes out of the signature. In this report, a new gene signature for TNBC is proposed. To our knowledge, this is the first TNBC signature that describes genes involved in general metabolism. The findings may be pertinent for Mexican patients and require evaluation in other ethnic groups and populations.

Abstract Background Male EBP disorder with neurologic defects (MEND) syndrome is an X‐linked disease caused by hypomorphic mutations in the EBP (emopamil‐binding protein) gene. Modifier genes may explain the clinical variability among individuals who share a primary mutation. Methods We studied four males (Patient 1 to Patient 4) exhibiting a descending degree of phenotypic severity from a family with MEND syndrome. To identify candidate modifier genes that explain the phenotypic variability, variants of homeostasis cholesterol genes identified by whole‐exome sequencing (WES) were ranked according to the predicted magnitude of their effect through an in‐house scoring system. Results Twenty‐seven from 105 missense variants found in 45 genes of the four exomes were considered significant (−5 to −9 scores). We found a direct genotype–phenotype association based on the differential accumulation of potentially functional gene variants among males. Patient 1 exhibited 17 variants, both Patients 2 and 3 exhibited nine variants, and Patient 4 exhibited only five variants. Conclusion We conclude that APOA5 (rs3135506), ABCA1 (rs9282541), and APOB (rs679899 and rs12714225) are the most relevant candidate modifier genes in this family. Relative accumulation of the deficiencies associated with variants of these genes along with other lesser deficiencies in other genes appears to explain the variable expressivity in MEND syndrome.

Background: Excess body weight has become a major public health problem worldwide, and the burden of overweight and obesity was calculated in this work from a health economics perspective. Objective: To estimate the burden of disease attributable to overweight and obesity among males and females aged 20 years and older using years of life lost (YLL) and age-standardized YLL rates (ASYLL), and to rank the leading causes of premature death. Design: A cross-sectional study took place (2010–2014) and 6,054 deaths were analyzed. Thirteen basic causes of death associated with overweight or obesity were included. The population attributable fraction (PAF), YLL, and ASYLL were calculated. Results: The overall burden attributable to overweight and obesity was 36,087 YLL, and the estimated ASYLL per 10,000 persons was 1,098 and 1,029 in males and females, respectively. Type 2 diabetes mellitus was the main cause of premature death (males, 968 ASYLL; females, 772 ASYLL). Conclusions: Overweight and obesity are major risk factors of chronic diseases that are main causes of premature death in the study population. Strategies for preventing overweight and obesity may decrease the incidence and mortality associated with these non-communicable diseases. ASYLL seems to be an indicator that is particularly well adapted to decision-making in public health.

Metabolic syndrome (MS) has been associated with testicular damage. Nonalcoholic fatty liver disease (NAFLD) is a multisystemic disease that affects different organs, but its effect on the testes is unknown. A study analyzing germ cell involvement on BALB/c mice was carried out. A parallel comparative study was conducted that investigated alterations in the germinal epithelium of male humans that died from an unrelated acute event. The complete medical histories and histologic samples of the thoracic aorta, liver tissue, and testicular tissue from the deceased subjects were collected. The degree of germinal epithelial loss (DGEL) was evaluated and the clinical and histologic data were compared between individuals with and without NAFLD. The only metabolic or morphologic variable that caused a significant difference in the DGEL, in both the animal model and humans, was the presence of liver steatosis. The percentage of steatosis was also correlated with the percentage of the DGEL. In humans, steatosis (greater than 20%) increased the risk 12-fold for presenting with a severe DGEL (OR: 12.5; 95% CI [1.2, 128.9]; p = .03). There was no association with age above 50 years or MS components. Steatosis grade was also correlated with atherosclerosis grade. NAFLD was a strongly associated factor implicated in severe DGEL, as well as the testis was identified as a probable target organ for damage caused by the disease. This finding could result in the search for new approach strategies in the management of men with fertility problems. Further studies are required to confirm these results.

BACKGROUND: Chemerin, encoded by the retinoic acid receptor responder 2 (RARRES2) gene is an adipocytesecreted protein with autocrine/paracrine functions in adipose tissue, metabolism and inflammation with a recently described function in vascular tone regulation, liver, steatosis, etc. This molecule is believed to represent a critical endocrine signal linking obesity to diabetes. There are no data available regarding evolution of RARRES2 in non-human primates and great apes. Expression profile and orthology in RARRES2 genes are unknown aspects in the biology of this multigene family in primates. Thus; we attempt to describe expression profile and phylogenetic relationship as complementary knowledge in the function of this gene in primates. To do that, we performed A RT-PCR from different tissues obtained during necropsies. Also we tested the hypotheses of positive evolution, purifying selection, and neutrality. And finally a phylogenetic analysis was made between primates RARRES2 protein. RESULTS: RARRES2 transcripts were present in liver, lung, adipose tissue, ovary, pancreas, heart, hypothalamus and pituitary tissues. Expression in kidney and leukocytes were not detectable in either species. It was determined that the studied genes are orthologous. CONCLUSIONS: RARRES2 evolution fits the hypothesis of purifying selection. Expression profiles of the RARRES2 gene are similar in baboons and chimpanzees and are also phylogenetically related.

BACKGROUND: Pure mucinous adenocarcinoma of the breast is a rare entity characterized by the production of variable amounts of mucin comprising 1% to 6% of breast carcinomas. Some mucinous adenocarcinomas have shown expression of intestinal differentiation markers such as MUC-2. This study examines the expression of intestinal differentiation markers in this type of breast carcinoma. RESULTS: Twenty-two cases of pure mucinous adenocarcinoma of the breast were assessed. Immunochemistry was performed for beta-catenin, CDX-2 and MUC-2. All cases were positive for B-catenin. MUC-2 positivity was observed in all cases; 63. 6% were 3 plus positive. All cases were negative for CDX-2. CONCLUSIONS: These results suggest that mucinous breast carcinomas express some markers of intestinal differentiation, such as MUC-2 and beta-catenin; however, future studies with a larger series of cases and using molecular techniques that help affirm these results are needed.

Renal cell carcinoma is the most common malignancy of the kidney in adults. In children, however, it only accounts for an estimated 1.8 to 6.3% of all pediatric malignant renal tumors. Papillary renal cell carcinoma is the second most common type of renal cell carcinoma in children. We present the case of a 12-year-old boy with a 2-month history of abdominal pain, unexplained weight loss, and gross hematuria. Computed tomography revealed a horseshoe kidney and a well-defined mass of 4 cm arising from the lower pole of the right kidney. Microscopically the tumor was composed of papillae covered with cells with abundant eosinophilic cytoplasm and high-grade nuclei with prominent nucleoli. Immunohistochemistry was performed; EMA, Vimentin, and AMACR were strongly positive while CK7, CD10, RCC antigen, TFE3, HMB-45, and WT-1 were negative. Currently, 10 months after the surgical procedure, the patient remains clinically and radiologically disease-free.

Cervical carcinoma is the most common malignancy of the female genital tract and represents the second most common malignancy in women worldwide. Histologically 85 to 90% of cervical cancers are squamous cell carcinoma. Osteoclastic giant cell rich squamous cell carcinoma is an unusual histological variant of which only 4 cases have been reported. We present the case of a 49-year-old woman with a 6-month history of irregular vaginal bleeding. Examination revealed a 2.7 cm polypoid mass in the anterior lip of the uterine cervix. The patient underwent hysterectomy with bilateral salpingo-oophorectomy. Microscopically the tumor was composed of infiltrative nests of poorly differentiated nonkeratinizing squamous cell carcinoma. Interspersed in between these tumor cells were numerous osteoclastic giant cells with abundant eosinophilic cytoplasm devoid of nuclear atypia, hyperchromatism, or mitotic activity. Immunohistochemistry was performed; CK and P63 were strongly positive in the squamous component and negative in the osteoclastic giant cells, while CD68 and Vimentin were strongly positive in the giant cell population and negative in the squamous component. The patient received chemo- and radiotherapy for recurrent disease identified 3 months later on a follow-up CT scan; 7 months after the surgical procedure the patient is clinically and radiologically disease-free.

ABSTRACT Coccidioidomycosis is an endemic disease of arid regions in the Western hemisphere. Its clinical presentation varies from asymptomatic nodules on chest x-rays to disseminated disease. We present the case of a 48-year-old man with a hard and heterogeneous tumor in the posterior aspect of the right testis. Color flow doppler testicular ultrasonography was performed and two nodular masses in the tail of the right epididymis were identified. An epididymectomy was performed and histopathological examination revealed coccidioidomycosis. After diagnosis, the patient was successfully treated with fluconazol.

Tumors of the paratesticular region are generally tumors of slow growth, with little symptomatology and, in most cases, benign in nature; in this area, a borderline serous tumor may arise hypothetically from Müllerian metaplasia of the tunica vaginalis, which is histologically identical to its ovarian counterpart. We present a 10-year-old male, with right gynecomastia and ipsilateral hydrocele, showing an enlarged right testicle with a volume of 12 ml and a left testicle with a volume of 10 ml. A right orchiectomy was performed, which presented a poorly defined tan tumor of 1.8 cm that occupied the vaginal and epididymal tunica, and infiltrates the testicular parenchyma. Histological sections revealed a cystic neoplasm, with hierarchical papillary projections, covered by one or several epithelial columnar and hobnail cells with moderate atypia and scant mitosis. Immunohistochemical reactions were performed, resulting positive for PAX-8, epithelial membrane antigen, and CK7, confirming the diagnosis of borderline serous tumor. Since the first reported case in 1986, few have been reported, the majority of these in adults with only three cases in children. In the few cases reported, the prognosis is usually favorable after surgical resection, with disease-free follow-up for up to 18 years. [ABSTRACT FROM AUTHOR]

Copyright of Patologia Revista Latinoamericana is the property of Asociacion Latinoamericana de Patologia/Asociacion Mexicana de Patologia/Consejo Mexicano de Medicos and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Patologia Revista Latinoamericana is the property of Asociacion Latinoamericana de Patologia/Asociacion Mexicana de Patologia/Consejo Mexicano de Medicos and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Copyright of Patologia Revista Latinoamericana is the property of Asociacion Latinoamericana de Patologia/Asociacion Mexicana de Patologia/Consejo Mexicano de Medicos and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Metastases to the breast are unusual lesions that make up approximately 2% of all malignant mammary neoplasms and may mimic both benign and malignant primary neoplasms from a clinical point of view, as well as in imaging studies. Arriving at a correct diagnosis is therefore essential in order to establish appropriate management. We present three cases of metastatic neoplasms diagnosed through fine needle aspiration biopsy and immunocytochemistry. The cytological diagnoses were: medulloblastoma in an 18-year-old woman, melanoma in a 26-year-old man, and an exceptional case of ovarian sarcoma originating from a granulosa cell tumor with metastases to both breasts. A metastatic disease should be considered in the differential diagnosis of a palpable mass in the breast, especially if there is a history of an extramammary malignant neoplasm. Fine needle aspiration biopsy is the method of choice for the management of these cases. Whenever possible the exam of the material obtained should be compared to the previous biopsy, which is usually enough to arrive at a correct diagnosis, thus preventing unnecessary surgical procedures. [ABSTRACT FROM AUTHOR]

Introduction: The preoperative marking of different breast lesions can be done using several methods. The aqueous carbon suspension (ACS) used as a marker, is a simple and low cost technique. Clinical case: The case of a 47-year old female patient who comes presenting a BIRADS 4 lesion in the upper internal quadrant of the right breast previously, identified through a mammography. A marking was done through a sonogram guided ACS. The General Surgery Service performed the excision of the marked tissue, corroborating the presence of the lesion and of the carbon in the excised tissue. The path report identified fibrocystic changes. The carbon did not interfere with its evaluation. Conclusion: The preoperative marking with ACS has several advantages: it is performed as an outpatient procedure with local anesthesia and allowing the surgical excision during the next three weeks. The identification of the lesion by the surgeon and the pathologist is more precise, apart from being less costly. [ABSTRACT FROM AUTHOR]