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Benefits of stereotactic radiosurgery (SRS) have been well established in melanoma brain metastases (MBM). Immunotherapy agents such as ipilimumab (ipi) have recently demonstrated clinical efficacy in advanced disease as well. The theoretical synergistic effects of combining these therapies in MBM have not been explored in detail, however, we conducted a systematic review with meta-analysis of studies that compared combined SRS and ipi versus SRS alone in MBM. Medical Literature Analysis and Retrieval System Online (MEDLINE) and Central databases were used for our literature search, which was conducted by three reviewers. We included studies that examined SRS and ipilimumab compared to SRS alone in MBM. Pertinent results were tabulated in a standardized spreadsheet. Newcastle-Ottawa Scale (NOS) Risk of Bias Assessment and Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method for rating evidence quality were used for qualitative analysis. Review Manager was used for statistical analysis. We identified four cohort studies that compared SRS plus ipi versus SRS alone in MBM. As per the GRADE criteria, we found low-quality evidence for survival benefits associated with combined treatment. Meta-analysis confirmed a significant benefit in survival for SRS and ipilimumab (hazard ratio 0.38, 95% confidence interval 0.28 - 0.52, p < 0.01). There were no significant differences between comparison groups for local control, distant brain control, radiation necrosis, or intracranial bleeding. We conclude that low-quality evidence exists for superior overall survival in MBM treated with SRS and ipilimumab compared to SRS without ipilimumab. There is also no increased risk of radiation necrosis and/or intracranial bleeding with combining radiation and immunotherapy in this setting.

Decreased testosterone levels in men are often a normal sign of aging. Testosterone replacement therapy (TRT) is a well-established option for those with symptomatic hypogonadism related to low testosterone levels. Conversely, designer herbal supplements in the context of testosterone supplementation are poorly studied, yet remain popular among aging men who seek the well-known, often enhancing, effects of testosterone that involve muscle mass and sexual function/drive. In 2014, the Food and Drug Administration (FDA) issued a warning about the significant risk of venous clots secondary to testosterone product use. Testosterone-induced polycythemia is one of the proposed mechanisms for this increased clotting propensity. Increased thromboxane A2 receptor density on platelets and increased platelet aggregation have also been linked to testosterone treatment in men. Fenugreek extract is a common active ingredient in commercially available herbal supplements that are often marketed as testosterone enhancers. It is thought that certain fenugreek compounds inhibit aromatase and 5-alpha-reductase activity, leading to diminished testosterone breakdown. However, the efficacy and safety profile of this agent in its use for boosting testosterone levels are unclear. In this case report, we present a patient with new-onset, bilateral pulmonary embolism possibly associated with the daily use of fenugreek-containing testosterone supplements.

Metastatic triple-negative breast cancer (TNBC) constitutes a heterogeneous group of diseases with systemic treatment options limited to cytotoxic chemotherapy at the time being. The disease tends to affect visceral organs more frequently when compared to hormone receptor-positive breast cancer. The prognoses of patients with heavily pretreated disease affecting the liver are very dismal. We present the response to radioembolization and systemic chemotherapy in a seriously ill patient who had undergone previous lines of chemotherapy for TNBC with extensive liver metastases.

Objective: To evaluate the effectiveness and tolerability of neoadjuvant chemotherapy with weekly paclitaxel in combination with weekly carboplatin area under curve 2 followed by anthracycline chemotherapy. Patients and methods: This is a retrospective review of electronic medical records of patients (N = 32) with stage 1c–III triple-negative breast cancer. Patients received neoadjuvant chemotherapy with paclitaxel 80 mg/m2 once per week for 12 weeks in combination with carboplatin area under curve 2 once per week for 12 weeks (wP + wCb), followed by a standard anthracycline regimen including either doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2 every 2 or 3 weeks, or epirubicin 90 mg/m2 and cyclophosphamide 600 mg/m2 every 3 weeks for four cycles with myeloid growth factor support. Results: Most patients (91%) received all 12 cycles of wP + wCb, and 88% received all four planned cycles of anthracycline chemotherapy. Of the patients, 84% completed all planned therapies. The complete pathologic response rate was 60%. In terms of hematologic toxicity, 96% of the patients experienced grade ≥3 leucopenia, 40% grade ≥3 anemia, and 15% grade ≥3 thrombocytopenia, and neutropenic fever was seen in 22% of the patients. Conclusion: The combination of neoadjuvant chemotherapy with wP + wCb before anthracycline chemotherapy can be tolerated by patients with triple-negative breast cancer. Complete pathologic response rates were comparable with those historically seen. Careful selection of patients is fundamental as this regimen is associated with a high incidence of hematologic toxicity. Keywords: Triple negative breast cancer, Neoadjuvant chemotherapy

Endocrine therapy (ET) is the usual first-line therapy for patients with hormone receptor-positive metastatic breast cancer (HR+MBC). However, resistance to ET frequently occurs during the course of treatment. Cellular pathways involved in cell proliferation are targets for new drugs that interfere with development of resistance to ET. Cyclin-dependent kinases (CDKs) are a subgroup of serine/ threonine kinases that play a key role in regulating cell cycle progression. In this review, we discuss the currently approved and under investigation CDK 4/6 inhibitors, in addition to their preclinical data and clinical trials that demonstrated their benefit in the treatment of HR+ breast cancer.

The vast majority of new HIV infections result from relatively inefficient transmission of the virus across mucosal surfaces during sexual intercourse. A consequence of this inefficiency is that small numbers of transmitted founder viruses initiate most heterosexual infections. This natural bottleneck to transmission has stimulated efforts to develop interventions that are aimed at blocking this step of the infection process. Despite the promise of this strategy, clinical trials of preexposure prophylaxis have had limited degrees of success in humans, in part because of lack of adherence to the recommended preexposure treatment regimens. In contrast, a number of existing vaccines elicit systemic immunity that protects against mucosal infections, such as the vaccines for influenza and human papilloma virus. We recently demonstrated the ability of vectored immunoprophylaxis (VIP) to prevent intravenous transmission of HIV in humanized mice using broadly neutralizing antibodies. Here we demonstrate that VIP is capable of protecting humanized mice from intravenous as well as vaginal challenge with diverse HIV strains despite repeated exposures. Moreover, animals receiving VIP that expresses a modified VRC07 antibody were completely resistant to repetitive intravaginal challenge by a heterosexually transmitted founder HIV strain, suggesting that VIP may be effective in preventing vaginal transmission of HIV between humans.

Various retinal degenerative diseases including dry and neovascular age-related macular degeneration (AMD), retinitis pigmentosa, and diabetic retinopathy are associated with the degeneration of the retinal pigmented epithelial (RPE) layer of the retina. This consequently results in the death of rod and cone photoreceptors that they support, structurally and functionally leading to legal or complete blindness. Therefore, developing therapeutic strategies to preserve cellular homeostasis in the RPE would be a favorable asset in the clinic. The aryl hydrocarbon receptor (AhR) is a conserved, environmental ligand-dependent, per ARNT-sim (PAS) domain containing bHLH transcription factor that mediates adaptive response to stress via its downstream transcriptional targets. Using in silico, in vitro and in vivo assays, we identified 2,2′-aminophenyl indole (2AI) as a potent synthetic ligand of AhR that protects RPE cells in vitro from lipid peroxidation cytotoxicity mediated by 4-hydroxynonenal (4HNE) as well as the retina in vivo from light-damage. Additionally, metabolic characterization of this molecule by LC-MS suggests that 2AI alters the lipid metabolism of RPE cells, enhancing the intracellular levels of palmitoleic acid. Finally, we show that, as a downstream effector of 2AI-mediated AhR activation, palmitoleic acid protects RPE cells from 4HNE-mediated stress, and light mediated retinal degeneration in mice.

Maple Syrup Urine Disease (MSUD) is an inherited disorder caused by the dysfunction in the branched chain keto-acid dehydrogenase (BCKDH) enzyme. This leads to buildup of branched-chain keto-acids (BCKA) and branched-chain amino acids (BCAA) in body fluids (e.g. keto-isocaproic acid from the BCAA leucine), leading to numerous clinical features including a less understood skeletal muscle dysfunction in patients. KIC is an inhibitor of mitochondrial function at disease relevant concentrations. A murine model of intermediate MSUD (iMSUD) shows significant skeletal muscle dysfunction as by judged decreased muscle fiber diameter. MSUD is an orphan disease with a need for novel drug interventions. Here using a 96-well plate (liquid chromatography- mass spectrometry (LC-MS) based drug-screening platform we show that Metformin, a widely used anti-diabetic drug, reduces levels of KIC in patient-derived fibroblasts by 20–50%. This Metformin-mediated effect was conserved in vivo; Metformin-treatment significantly reduced levels of KIC in the muscle (by 69%) and serum (by 56%) isolated from iMSUD mice and restored levels of mitochondrial metabolites (e.g. AMP and other TCA). The drug also decreased the expression of mitochondrial branched chain amino transferase (BCAT) which produces KIC in skeletal muscle. This suggests that Metformin can restore skeletal muscle homeostasis in MSUD by decreasing mitochondrial KIC production.

Background: Long-term lithium use in psychiatric patients may lead to lithium associated hyperparathyroidism (LAH). Although anecdotal case reports have appeared, an evidence based algorithm for management of LAH is lacking. Methods: A comprehensive literature search was performed (1973-2010) using PubMed with keywords; “lithium” “hypercalcemia” “hyperparathyroidism” “sestamibi” “intra-operative parathyroid hormone (IOPTH) monitoring” “parathyroidectomy” and “medical management”. All English language publications addressing etiology and clinical management issues concerning LAH were critically analyzed. Results: Lithium associated hyperparathyroidism occurs in 4.3% - 6.3% of chronic lithium users compared to the general population which has an incidence of 0.5% - 1%. 194 cases of LAH have been reported which includes 10 patients (5%) treated medically and 170 patients (88%) who underwent parathyroidectomy. No details were available for 14 patients (7%). Among parathyroidectomy patients, 104 (59%) had adenomatous disease and 66 (39%) had multiglandular hyperplasia. Preoperative localization studies were utilized in only 22 patients (13%) and IOPTH monitoring was reported in only 3 studies (32 patients, 19%). Among surgical patients, bilateral neck exploration (BNE) was the most common approach performed in 162 patients (95%); focused neck exploration was utilized in only 8 patients (5%). Parathyroidectomy normalized LAH biochemical changes in nearly all patients (90% - 97%) in the early post-operative period, but recurrent hyperparathyroidism occurred in 8% - 42% of patients. Conclusion: LAH is an under appreciated and poorly understood endocrine disorder. LAH has a higher incidence of multiglandular disease and bilateral neck exploration is mandatory in majority for disease control. Nonsurgical approaches may be useful in select patients on short-term lithium therapy.

The flagellum of African trypanosomes is an essential and multifunctional organelle that functions in motility, cell morphogenesis, and host-parasite interaction. Previous studies of the trypanosome flagellum have been limited by the inability to purify flagella without first removing the flagellar membrane. This limitation is particularly relevant in the context of studying flagellum signaling, as signaling requires surface-exposed proteins in the flagellar membrane and soluble signaling proteins in the flagellar matrix. Here we employ a combination of genetic and mechanical approaches to purify intact flagella from the African trypanosome, Trypanosoma brucei, in its mammalian-infectious stage. We combined flagellum purification with affinity-purification of surface-exposed proteins to conduct independent proteomic analyses of the flagellum surface and matrix fractions. The proteins identified encompass a broad range of molecular functionalities, including many predicted to function in signaling. Immunofluorescence and RNA interference studies demonstrate flagellum localization and function for proteins identified and provide insight into mechanisms of flagellum attachment and motility. The flagellum surface proteome includes many T. brucei-specific proteins and is enriched for proteins up-regulated in the mammalian-infectious stage of the parasite life-cycle. The combined results indicate that the flagellum surface presents a diverse and dynamic host-parasite interface that is well-suited for host-parasite signaling.