The Importance of Safely Prescribing Hormones in the Transgender Community.

The transgender community is rapidly growing, necessitating further education and understanding of their unique healthcare needs. Gender affirmation is a multistep process, which generally begins with transgender individuals socially transitioning by adopting a new name, pronouns, and appearance changes, such as hair and clothing, to express themselves. Additional gender affirmation treatment can be achieved through medical therapy with hormones and surgical intervention. Here, we report the case of an 18-year-old transgender man who presented to his primary care provider for a referral to initiate a medical transition with testosterone therapy. The patient practiced penetrative vaginal sex without contraception. The patient presented to the clinic eight months later with amenorrhea, thick coarse facial and body hair, oily skin, irritable moods, and a 20-lb weight gain. A pregnancy test revealed a positive result. A healthy baby girl was delivered at 40 weeks' gestation. This case demonstrates the importance of addressing contraception during the masculinization process in individuals who continue to practice vaginal intercourse. Healthcare providers should seek to establish a clinical environment free of discrimination and stigma to allow patients to feel comfortable describing potential triggers of gender dysphoria. We encourage medical practitioners to discuss all methods of birth control with transgender male patients and choose the contraceptive that best allows for a seamless medical transition.

A Case of Dulaglutide-Induced Vaginal Bleed.

Type 2 diabetes mellitus (T2DM) is a growing challenge across the globe. The disease process is amendable to lifestyle modifications in the early stages. If those changes fail to correct endocrine dysfunction, medical therapy is initiated. Initially, therapy for type 2 diabetes consisted of biguanides and sulfonylureas. With modern medicine, we have developed dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter-2 inhibitors, and glucagon-like peptide 1 (GLP-1) receptor agonists. Dulaglutide is a GLP-1 receptor agonist that is sold under the brand name Trulicity. The most common side effect associated with Dulaglutide is gastrointestinal discomfort. We present a case of severe vaginal bleeding due to a rare side effect of Dulaglutide. A 44-year-old perimenopausal female with a past medical history of type 2 diabetes mellitus presented to the clinic after experiencing significant vaginal bleeding. The patient was unable to tolerate Metformin and Semaglutide in the past. The abnormal vaginal hemorrhage started one week after receiving the second dose of Dulaglutide. Her hemoglobin concentration fell significantly. Dulaglutide was immediately discontinued, and her vaginal bleeding stopped. This case documents the necessity of post-market surveillance to oversee the safety of recently approved medications by the Food and Drug Administration (FDA). Rare side effects can emerge in the general population that were not seen during clinical trials. Physicians should consider the possibility of adverse medication reactions when determining whether to start a new medication or a conventional one.

Different Sensitivity of Advanced Bronchial and Alveolar Mono- and Coculture Models for Hazard Assessment of Nanomaterials.

For the next-generation risk assessment (NGRA) of chemicals and nanomaterials, new approach methodologies (NAMs) are needed for hazard assessment in compliance with the 3R's to reduce, replace and refine animal experiments. This study aimed to establish and characterize an advanced respiratory model consisting of human epithelial bronchial BEAS-2B cells cultivated at the air-liquid interface (ALI), both as monocultures and in cocultures with human endothelial EA.hy926 cells. The performance of the bronchial models was compared to a commonly used alveolar model consisting of A549 in monoculture and in coculture with EA.hy926 cells. The cells were exposed at the ALI to nanosilver (NM-300K) in the VITROCELL® Cloud. After 24 h, cellular viability (alamarBlue assay), inflammatory response (enzyme-linked immunosorbent assay), DNA damage (enzyme-modified comet assay), and chromosomal damage (cytokinesis-block micronucleus assay) were measured. Cytotoxicity and genotoxicity induced by NM-300K were dependent on both the cell types and model, where BEAS-2B in monocultures had the highest sensitivity in terms of cell viability and DNA strand breaks. This study indicates that the four ALI lung models have different sensitivities to NM-300K exposure and brings important knowledge for the further development of advanced 3D respiratory in vitro models for the most reliable human hazard assessment based on NAMs.

Breaking Healthcare Barriers for Transgender Individuals With Rare Tumor Presentation.

Transgender persons can experience healthcare barriers and potentially suffer from preventable health disparities. Some challenges these individuals may face include the lack of provider education, social stigma, socioeconomic barriers to care, and insurance instability. Combating this problem requires systemic changes. Unfortunately, there are limited data on providers' perspective on taking care of transgender persons, and healthcare delivery systems are often unequipped to adequately manage these patients. This case presentation exemplifies many of these challenges. A 47-year-old transgender female with a history of testicular cancer, presented with bleeding from a lump on her neck. A computed tomography (CT) scan of the neck revealed a large mass suspicious of malignancy. Pathology identified metastatic colorectal adenocarcinoma. Esophagogastroduodenoscopy, colonoscopy, positron emission tomography scan, CT abdomen/pelvis, and serum tumor marker showed no evidence of a primary gastrointestinal malignancy. This presentation likely represents a late relapse of a residual, metastatic germ cell tumor with malignant somatic transformation. This case was greatly impacted by social determinants of health. The patient did not identify with her male anatomy, which delayed the detection of the initial testicular malignancy. In the post-operative period, the patient did not attend follow-up appointments to avoid discussing her male genitalia. When tumor relapse did occur, the patient experienced financial, insurance, and transportation instability; this delayed medical care and allowed the mass to grow to an extraordinary size.

Death domain-associated protein (DAXX) expression is associated with poor survival in metastatic high-grade serous carcinoma.

The objective of this study was to analyze the expression and clinical role of mitosis regulators α-thalassemia/mental retardation syndrome X-linked (ATRX) and death-domain-associated protein (DAXX) in metastatic high-grade serous carcinoma (HGSC). ATRX and DAXX protein expression by immunohistochemistry was analyzed in 400 HGSC effusions. DAXX expression was additionally studied in 15 cancer cell lines, including 4 ovarian carcinoma lines, and in 81 of the 400 HGSC effusions using Western blotting. ATRX and DAXX were expressed in HGSC cells in 386/400 (96%) and 348/400 (87%) effusions, respectively. Western blotting showed DAXX expression in all 15 cell lines and in 70/81 (86%) HGSC effusions. DAXX expression by immunohistochemistry was higher in pleural compared to peritoneal effusions (p = 0.006) and in post-chemotherapy compared to pre-chemotherapy effusions (p = 0.004), and its expression was significantly associated with poor overall survival in univariate of the entire cohort (p = 0.014), as well as analysis limited to chemo-naïve effusions tapped at diagnosis (p = 0.038). The former association retained its prognostic role in Cox multivariate survival analysis (p = 0.011). ATRX expression was unrelated to clinicopathologic parameters or survival. In conclusion, DAXX is associated with disease progression and could be a prognostic marker in metastatic HGSC. Silencing this molecule may have therapeutic relevance in this cancer.

Soluble AXL as a marker of disease progression and survival in melanoma.

Receptor tyrosine kinase AXL is a one-pass transmembrane protein upregulated in cancers and associated with lower survival and therapy resistance. AXL can be cleaved by the A Disintegrin and Metalloproteinases (ADAM)10 and ADAM17, yielding a soluble version of the protein. Elevated soluble AXL (sAXL) has been reported to be associated with disease progression in hepatocellular carcinoma, renal cancer, neurofibromatosis type 1 and inflammatory diseases. In the present work, we analyzed sAXL levels in blood from melanoma patients and showed that sAXL increases with disease progression. Additionally, increased sAXL levels were found correlated with shorter two-year survival in stage IV patients treated with ipilimumab. Furthermore, we showed that sAXL levels were related to the percentage of cells expressing AXL in resected melanoma lymph node metastases. This finding was verified in vitro, where sAXL levels in the cell media corresponded to AXL expression in the cells. AXL inhibition using the small-molecular inhibitor BGB324 reduced sAXL levels, while the cellular expression was elevated through increased protein stability. Our findings signify that quantification of sAXL blood levels is a simple and easily assessable method to determine cellular AXL levels and should be further evaluated for its use as a biomarker of disease progression and treatment response.

Targeting AXL and the DNA Damage Response Pathway as a Novel Therapeutic Strategy in Melanoma.

Receptor tyrosine kinase AXL is found upregulated in various types of cancer, including melanoma, and correlates with an aggressive cancer phenotype, inducing cell proliferation and epithelial-to-mesenchymal transition. In addition, AXL has recently been linked to chemotherapy resistance, and inhibition of AXL is found to increase DNA damage and reduce expression of DNA repair proteins. In light of this, we aimed to investigate whether targeting AXL together with DNA damage response proteins would be therapeutically beneficial. Using melanoma cell lines, we observed that combined reduction of AXL and CHK1/CHK2 signaling decreased proliferation, deregulated cell-cycle progression, increased apoptosis, and reduced expression of DNA damage response proteins. Enhanced therapeutic effect of combined treatment, as compared with mono-treatment, was further observed in a patient-derived xenograft model and, of particular interest, when applying a three-dimensional ex vivo spheroid drug sensitivity assay on tumor cells harvested directly from 27 patients with melanoma lymph node metastases. Together, these results indicate that targeting AXL together with the DNA damage response pathway could be a promising treatment strategy in melanoma, and that further investigations in patient groups lacking treatment alternatives should be pursued.

A Three-dimensional Ex Vivo Viability Assay Reveals a Strong Correlation Between Response to Targeted Inhibitors and Mutation Status in Melanoma Lymph Node Metastases.

Although clinical management of melanoma has changed considerably in recent years, intrinsic treatment resistance remains a severe problem and strategies to design personal treatment regimens are highly warranted. We have applied a three-dimensional (3D) ex vivo drug efficacy assay, exposing disaggregated cells from 38 freshly harvested melanoma lymph node metastases and 21 patient derived xenografts (PDXs) to clinical relevant drugs for 7 days, and examined its potential to evaluate therapy response. A strong association between Vemurafenib response and BRAF mutation status was achieved (P < .0001), while enhanced viability was seen in some NRAS mutated tumors. BRAF and NRAS mutated tumors responded comparably to the MEK inhibitor Cobimetinib. Based on the ex vivo results, two tumors diagnosed as BRAF wild-type by routine pathology examinations had to be re-evaluated; one was subsequently found to have a complex V600E mutation, the other a double BRAF mutation (V600E/K601 N). No BRAF inhibitor resistance mechanisms were identified, but PIK3CA and NF1 mutations were identified in two highly responsive tumors. Concordance between ex vivo drug responses using tissue from PDXs and corresponding patient tumors demonstrate that PDX models represent an indefinite source of tumor material that may allow ex vivo evaluation of numerous drugs and combinations, as well as studies of underlying molecular mechanisms. In conclusion, we have established a rapid and low cost ex vivo drug efficacy assay applicable on tumor tissue from patient biopsies. The 3D/spheroid format, limiting the influence from normal adjacent cells and allowing assessment of drug sensitivity to numerous drugs in one week, confirms its potential as a supplement to guide clinical decision, in particular in identifying non-responding patients.

Soluble AXL is ubiquitously present in malignant serous effusions.

OBJECTIVE: The objective of this study was to analyze the expression level and clinical role of soluble AXL (sAXL) in cancers affecting the serosal surfaces, with focus on ovarian carcinoma. METHODS: sAXL protein expression by ELISA was analyzed in 572 effusion supernatants, including 424 peritoneal, 147 pleural and 1 pericardial specimens. RESULTS: sAXL was overexpressed in peritoneal effusions compared to pleural and pericardial specimens (p < 0.001). sAXL levels were additionally significantly higher in effusions from patients with ovarian carcinoma, malignant mesothelioma and breast carcinoma compared to specimens from patients with other cancers (predominantly carcinomas of lung, gastrointestinal or uterine corpus/cervix origin) or benign reactive effusions (p < 0.001). sAXL was further overexpressed in high-grade serous carcinoma (HGSC; n = 373) compared to low-grade serous carcinoma (LGSC; n = 32; p = 0.036). In HGSC, sAXL levels were significantly lower in post-chemotherapy effusions compared to primary diagnosis pre-chemotherapy specimens (p = 0.002). sAXL levels in HGSC were unrelated to chemoresponse at diagnosis, progression-free survival or overall survival. Levels were similarly unrelated to survival in LGSC and breast carcinoma. CONCLUSIONS: sAXL is widely expressed in malignant effusions, particularly in ovarian and breast carcinoma and in malignant mesothelioma. sAXL is overexpressed in HGSC compared to LGSC and its levels are lower following exposure to chemotherapy. However, sAXL levels are not informative of chemoresponse or survival.

Retrospective review of predisposing factors and surgical outcomes in obstetric fistula patients at a single teaching hospital in Western Kenya.

OBJECTIVE: We examined success rates and complications of obstetric fistula (OF) surgical repairs in association with patient and fistula characteristics, including sociocultural and socioeconomic determinants of health. A better understanding of these associations will help guide surgical management and prevent predisposing factors. METHODS: We reviewed the medical records of 86 patients who underwent OF repair at Moi Teaching and Referral Hospital in Kenya between 1999 and 2007. RESULTS: Women with OF presented for repair with a variety of concurrent conditions. Seventy-eight percent had laboured for at least 24 hours; 29% had undergone previous unsuccessful surgery. Of the women who presented at postoperative follow-up, 54% still complained of incontinence. Persistent incontinence was associated with larger, more complicated fistulas and having had previous failed attempts at surgical repair. CONCLUSION: The association of factors such as duration of labour with OF reflects the limited availability of obstetrical care in Western Kenya. There is a significant difference in postoperative success of fistula repair between women with large fistulas or those who had previous failed surgery and other patients. This reflects the importance of primary and secondary prevention.

Defective somite patterning in mouse embryos with reduced levels of Tbx6.

During vertebrate embryogenesis, paraxial mesoderm gives rise to somites, which subsequently develop into the dermis, skeletal muscle, ribs and vertebrae of the adult. Mutations that disrupt the patterning of individual somites have dramatic effects on these tissues, including fusions of the ribs and vertebrae. The T-box transcription factor, Tbx6, is expressed in the paraxial mesoderm but is downregulated as somites develop. It is essential for the formation of posterior somites, which are replaced with ectopic neural tubes in Tbx6-null mutant embryos. We show that partial restoration of Tbx6 expression in null mutants rescues somite development, but that rostrocaudal patterning within them is defective, ultimately resulting in rib and vertebral fusions, demonstrating that Tbx6 activity in the paraxial mesoderm is required not simply for somite specification but also for their normal patterning. Somite patterning is dependent upon Notch signaling and we show that Tbx6 genetically interacts with the Notch ligand, delta-like 1 (Dll1). Dll1 expression, which is absent in the Tbx6-null mutant, is restored at reduced levels in the partially rescued mutants, suggesting that Dll1 is a target of Tbx6. We also identify the spontaneous mutation rib-vertebrae as a hypomorphic mutation in Tbx6. The similarity in the phenotypes we describe here and that of some human birth defects, such as spondylocostal dysostosis, raises the possibility that mutations in Tbx6 or components of this pathway may be responsible for these defects.