Pyruvate Dehydrogenase Kinase 4 Deficiency Increases Tumorigenesis in a Murine Model of Bladder Cancer.

Pyruvate dehydrogenase kinase 4 (PDK4) is a mitochondrial isozyme in the PDK family (PDK1-4) partially responsible for phosphorylation of pyruvate dehydrogenase (PDH). Phosphorylation of PDH is thought to result in a pro-proliferative shift in metabolism that sustains growth of cancer cells. Previous data from our lab indicate the pan-PDK inhibitor dichloroacetate (DCA) or acute genetic knockdown of PDK4 blocks proliferation of bladder cancer (BCa) cells. The goal of this study was to determine the role of PDK4 in an in vivo BCa model, with the hypothesis that genetic depletion of PDK4 would impair formation of BCa. PDK4-/- or WT animals were exposed to N-Butyl-N-(4-hydroxybutyl) nitrosamine (BBN) for 16 weeks, and tumors were allowed to develop for up to 7 additional weeks. PDK4-/- mice had significantly larger tumors at later time points. When animals were treated with cisplatin, PDK4-/- animals still had larger tumors than WT mice. PDK4 expression was assessed in human tissue and in mice. WT mice lost expression of PDK4 as tumors became muscle-invasive. Similar results were observed in human samples, wherein tumors had less expression of PDK4 than benign tissue. In summary, PDK4 has a complex, multifunctional role in BCa and may represent an underrecognized tumor suppressor.

PrEP patient attitudes, beliefs and perceived barriers surrounding HPV vaccination: a qualitative study of semistructured interviews with PrEP patients in primary care clinics in Kansas and Missouri.

OBJECTIVES: Men who have sex with men who use pre-exposure prophylaxis (PrEP) have not traditionally been targets for human papillomavirus (HPV) vaccine programmes, despite their high risk for HPV-related cancers and HPV vaccine being approved by the U.S. Food and Drug Administration (FDA) for people up to age 45. The objective of this study was to assess attitudes and barriers towards HPV vaccine for adult PrEP users in the primary care context. METHODS: Semistructured phone interviews of 16 primary care patients taking PrEP in the Kansas City metropolitan area were conducted, with interviews assessing HPV vaccination status, and attitudes, beliefs and perceived barriers surrounding HPV vaccine. Interview notes were open-coded by student authors, and themes were generated through code review and consensus. Data were then analysed using thematic analysis. RESULTS: The results showed that most patients believed that preventative health was important and felt the HPV vaccine was important. Most patients were open to vaccination if recommended by their primary care physician and covered by insurance. Most participants believed HPV infection to be far worse in women, and there were gaps in knowledge surrounding HPV and its effects in men. CONCLUSIONS: While more research is needed to better understand facilitators of a linkage between PrEP and HPV vaccine in clinical settings for groups at high risk for HPV-related cancers, getting primary care providers involved in educating high-risk patients about the importance of HPV vaccination and actively recommending the vaccine to those patients has the potential to prevent HPV-related cancers.

Testicular cancer presenting as disseminated tuberculosis: A case report.

Introduction and Importance: Tuberculosis is one of the leading infectious causes of mortality worldwide. In the United States, foreign-born persons account for 70% of tuberculosis (TB) diagnoses. Comparatively, testicular cancer is much less common. However, metastatic disease may present similarly. Diagnosis is supported by elevated tumor markers and radical orchiectomy with specimen biopsy confirms the diagnosis and tumor type. Following resection, adjuvant treatment for metastatic disease includes chemotherapy. Case Presentation: This case describes a 22-year-old male immigrant with shortness of breath as the presenting symptom. Chest imaging showed a cavitary lung lesion encroaching the bronchus and left atrium. The patient was placed on airborne precautions and a complex hospital course ensued which resulted in the diagnosis of metastatic nonseminomatous germ cell tumor. The patient's 8 cm testicular tumor was treated with radical orchiectomy followed by chemotherapy. His condition deteriorated quickly, and he passed away in the hospital. Clinical Discussion: Metastatic testicular cancer is relatively rare compared to tuberculosis, especially in the immigrant population. Differentiating extrapulmonary TB from metastatic disease can pose a diagnostic challenge due to similar presentations. Complete physical exam including the genitalia is paramount in discerning a diagnosis of testicular cancer. Conclusion: Incidence of metastatic testicular cancer is much less common than extrapulmonary tuberculosis but must always be included on the differential for a young male.

Gartner's duct cysts: a review of surgical management and a new technique using fluorescein dye.

INTRODUCTION AND HYPOTHESIS: Gartner's duct cysts (GDC) are benign lesions that may become symptomatic, leading to surgical intervention. There is no standard surgical technique for management of GDC. This article provides a comprehensive review of surgical the management of GDC. We also present a new technique using fluorescein dye to help delineate GDC walls and facilitate complete cyst excision. METHODS: We conducted a PubMed search for English-language articles without a defined time range. The search combined subject headings, title, abstract, and text words relating to Gartner duct cysts. Articles describing surgical management of GDC were included. Exclusion criteria included inadequate diagnosis of GDC, infected cysts, nonsurgical management, or article unavailable for interlibrary loan. A novel approach using intra-cyst fluorescein dye injection is described. RESULTS: Two hundred sixty-seven articles were identified via PubMed, and 34 articles were included in the review based on eligibility criteria. Concomitant genitourinary malformations occurred in 19 of the 92 surgically managed patients. Surgical techniques included cyst excision (50 patients), tetracycline injection following aspiration (15), marsupialization (14), unroofing/partial excision (9), and puncture/evacuation (4). Recurrences occurred in 4, 1, 0, 0, and 1 patient, respectively. One patient underwent uncomplicated fluorescein dye-assisted cyst excision with no recurrence 30 months post-procedure. CONCLUSIONS: The low incidence of GDCs necessitating surgical intervention has resulted in a lack of standard surgical technique, especially in patients with concurrent genitourinary malformations. Utilizing fluorescein dye provides a surgical method that can help confirm the absence of urologic involvement as well as facilitate precise excision of GDC.

Tumor M2-PK: A novel urine marker of bladder cancer.

PURPOSE: Bladder cancer is a "Warburg-like" tumor characterized by a reliance on aerobic glycolysis and expression of pyruvate kinase M2 (PKM2). PKM2 oscillates between an active tetramer and an inactive dimer. We aim to further characterize PKM2, in particular PKM2 dimer, as a urinary biomarker of bladder cancer and a potential target for treatment. METHODS: HTB-9, HTB-5, and UM-UC3 bladder cancer cells were assessed for proliferation under differential glucose levels using the hexosaminidase assay. Western blot and Blue-native analysis was performed for protein expression of PKM2. Shikonin, an herb that is known to bind and inhibit PKM2, was utilized to determine if PKM2 has a role in glucose usage and cellular proliferation in bladder cancer cells by caspase activity assay. Institutional review board approval was obtained to collect healthy control and bladder cancer patient urine samples. The ScheBo M2-PK EDTA Plasma Test was performed on urine samples to assess urine Tumor M2-PK values. RESULTS: The three bladder cancer cell lines tested all demonstrate statistically significant increases in proliferation when exposed to higher level of glucose (200mg/dL). Similarly, low doses of glucose (25mg/dL) result in reduced proliferation. Increased cell growth in higher glucose concentration correlated with up-regulation of PKM2 protein expression. Shikonin, a PKM2 inhibitor, reduced cell proliferation and switched PKM2 isoforms from the dimer to tetramer. Lastly, dimer PKM2 (Tumor-M2PK) levels were assessed in the urine samples from bladder cancer (Bca) patients and healthy controls. Tumor M2-PK significantly correlated with the presence of BCa in our subjects. CONCLUSIONS: Our studies demonstrate the potential of PKM2, specifically the dimer (Tumor-M2PK) as a target of drug therapy and as a urinary marker for bladder cancer.

Patterns of fluctuating asymmetry in the limbs of anurans.

It has been hypothesized that fluctuating asymmetry (FA) may provide an indication of the functional importance of structures within an organism, with structures that more strongly impact fitness being more symmetric. Based on this idea, we predicted that for tetrapods in which the forelimbs and hindlimbs play an unequal role in locomotion, the less functionally important limb set should display higher levels of FA. We conducted a multispecies test of this hypothesis in anurans (frogs and toads), whose saltatory locomotor mode is powered by the hindlimbs. We also tested whether FA in the forelimbs, which play a more important role during landing, differed between families that differ in the degree of forelimb use in locomotion (Bufonidae vs. Ranidae). We calculated FA from the lengths of humeri and femora measured from disarticulated skeletal specimens of four anuran taxa (Bufonidae: Anaxyrus americanus, Rhinella marina; Ranidae: Lithobates catesbeianus, Lithobates clamitans). Our findings were consistent with the hypothesis that natural selection for increased locomotor performance may influence patterns of FA seen in vertebrate limbs, with all species displaying lower mean FA in the hindlimbs. More subtle functional roles between the forelimbs of bufonids and ranids, however, did not elicit different levels of FA.