A Case of Budd-Chiari Syndrome Secondary to Tumor Thrombosis.

Budd-Chiari syndrome (BCS) is a rare constellation of conditions due to obstruction of venous flow from anatomical levels ranging from the hepatic veins to the confluence of the inferior vena cava (IVC) and right atrium. The resulting retrograde flow of blood leads to hepatomegaly, ascites, and liver failure among other features. Our case highlights the clinical features, diagnostic challenges, and management of a patient with a tumor thrombus from a metastatic prostate adenocarcinoma in a 67-year-old male leading to BCS. This patient, with a past history of prostate adenocarcinoma and aortic valve replacement on chronic warfarin anticoagulation, presented with acutely worsening abdominal pain and a distended abdomen, and imaging revealed an IVC filling defect. Subsequent imaging with a piflufolastat prostate-specific PET showing increased uptake in the IVC elucidated the diagnosis of tumor thrombosis. Management considerations include aggressive therapy and optimization of quality of life. The patient was offered both options, and options including surgical shunting, bypasses, and anticoagulation were discussed. After shared decision-making, the patient and family opted to choose the pathway of palliative radiation and anticoagulation.

Nicardipine is a putative EED inhibitor and has high selectivity and potency against chemoresistant prostate cancer in preclinical models.

BACKGROUND: It is imperative to develop novel therapeutics to overcome chemoresistance, a significant obstacle in the clinical management of prostate cancer (PCa) and other cancers. METHODS: A phenotypic screen was performed to identify novel inhibitors of chemoresistant PCa cells. The mechanism of action of potential candidate(s) was investigated using in silico docking, and molecular and cellular assays in chemoresistant PCa cells. The in vivo efficacy was evaluated in mouse xenograft models of chemoresistant PCa. RESULTS: Nicardipine exhibited high selectivity and potency against chemoresistant PCa cells via inducing apoptosis and cell cycle arrest. Computational, molecular, and cellular studies identified nicardipine as a putative inhibitor of embryonic ectoderm development (EED) protein, and the results are consistent with a proposed mechanism of action that nicardipine destabilised enhancer of zeste homologue 2 (EZH2) and inhibited key components of noncanonical EZH2 signalling, including transducer and activator of transcription 3, S-phase kinase-associated protein 2, ATP binding cassette B1, and survivin. As a monotherapy, nicardipine effectively inhibited the skeletal growth of chemoresistant C4-2B-TaxR tumours. As a combination regimen, nicardipine synergistically enhanced the in vivo efficacy of docetaxel against C4-2 xenografts. CONCLUSION: Our findings provided the first preclinical evidence supporting nicardipine as a novel EED inhibitor that has the potential to be promptly tested in PCa patients to overcome chemoresistance and improve clinical outcomes.

Bromocriptine monotherapy overcomes prostate cancer chemoresistance in preclinical models.

Chemoresistance is a major obstacle in the clinical management of metastatic, castration-resistant prostate cancer (PCa). It is imperative to develop novel strategies to overcome chemoresistance and improve clinical outcomes in patients who have failed chemotherapy. Using a two-tier phenotypic screening platform, we identified bromocriptine mesylate as a potent and selective inhibitor of chemoresistant PCa cells. Bromocriptine effectively induced cell cycle arrest and activated apoptosis in chemoresistant PCa cells but not in chemoresponsive PCa cells. RNA-seq analyses revealed that bromocriptine affected a subset of genes implicated in the regulation of the cell cycle, DNA repair, and cell death. Interestingly, approximately one-third (50/157) of the differentially expressed genes affected by bromocriptine overlapped with known p53-p21- retinoblastoma protein (RB) target genes. At the protein level, bromocriptine increased the expression of dopamine D2 receptor (DRD2) and affected several classical and non-classical dopamine receptor signal pathways in chemoresistant PCa cells, including adenosine monophosphate-activated protein kinase (AMPK), p38 mitogen-activated protein kinase (p38 MAPK), nuclear factor kappa B  (NF-κB), enhancer of zeste homolog 2 (EZH2), and survivin. As a monotherapy, bromocriptine treatment at 15 mg/kg, three times per week, via the intraperitoneal route significantly inhibited the skeletal growth of chemoresistant C4-2B-TaxR xenografts in athymic nude mice. In summary, these results provided the first preclinical evidence that bromocriptine is a selective and effective inhibitor of chemoresistant PCa. Due to its favorable clinical safety profiles, bromocriptine could be rapidly tested in PCa patients and repurposed as a novel subtype-specific treatment to overcome chemoresistance.

Overcoming prostate cancer drug resistance with a novel organosilicon small molecule.

A major challenge to the treatment of advanced prostate cancer (PCa) is the development of resistance to androgen-deprivation therapy (ADT) and chemotherapy. It is imperative to discover effective therapies to overcome drug resistance and improve clinical outcomes. We have developed a novel class of silicon-containing compounds and evaluated the anticancer activities and mechanism of action using cellular and animal models of drug-resistant PCa. Five organosilicon compounds were evaluated for their anticancer activities in the NCI-60 panel and established drug-resistant PCa cell lines. GH1504 exhibited potent in vitro cytotoxicity in a broad spectrum of human cancer cells, including PCa cells refractory to ADT and chemotherapy. Molecular studies identified several potential targets of GH1504, most notably androgen receptor (AR), AR variant 7 (AR-v7) and survivin. Mechanistically, GH1504 may promote the protein turnover of AR, AR-v7 and survivin, thereby inducing apoptosis in ADT-resistant and chemoresistant PCa cells. Animal studies demonstrated that GH1504 effectively inhibited the in vivo growth of ADT-resistant CWR22Rv1 and chemoresistant C4-2B-TaxR xenografts in subcutaneous and intraosseous models. These preclinical results indicated that GH1504 is a promising lead that can be further developed as a novel therapy for drug-resistant PCa.

Embryonic Ectoderm Development (EED) as a Novel Target for Cancer Treatment.

The polycomb repressive complex 2 (PRC2) can methylate at lysine 27 of histone H3 at the trimethylation level (H3K27me3). This leads to gene silencing and is known to be dysregulated in many cancers. PRC2 is made up of three core subunits: EZH2, SUZ12, and EED. EED is essential for the regulation of PRC2 function by binding to H3K27me3. Targeting the allosteric site within EED offers new strategies to disrupt the PRC2 activity. In this minireview, we summarize some of the recent developments in small molecules that target EED and its interaction with other core proteins in the PRC2 complex.

Interpretative characteristics and case features associated with the performances of radiologists in reading mammograms: A study from a non-screening population in Asia.

AIMS: To explore radiologist characteristics and case features associated with diagnostic performances in cancer detection on mammograms in a South East Asian population. METHODS: Fifty-three radiologists reported 60 mammographic examinations which consisted of 40 normal and 20 cancer-containing cases at the BREAST workshops. Radiologists were asked to examine each mammogram using the BIRADS on diagnostic monitors. Differences in reader characteristics and case features between correct and incorrect decisions were assessed separately for cancer and normal cases. Univariate and multivariate logistic regressions were applied to generate odds ratios (OR) for significant factors related to correct decisions. RESULTS: Radiologists who spent ≥10 hours/week reporting mammograms had a higher possibility of detecting cancer lesions (OR = 1.6; P = 0.01). A higher rate of accuracy in reporting negative cases was associated with female radiologists (OR = 1.4; P = 0.002), radiologists who read ≤20 mammograms per week (OR = 1.5; P < 0.0001), had completed training course (OR = 1.7; P < 0.0001) or wore eyeglasses (OR = 1.4; P = 0.01). Cancer cases with breast density >50% (OR = 2.1; P < 0.0001), having abnormal lesions ≥9 mm (OR = 1.8; P < 0.0001), or displaying calcifications, a discrete mass or nonspecific density (OR = 1.6; P < 0.0001) were recorded with a higher detection rate by radiologists than other cases. Lesions located on the right breasts (OR = 1.8; P < 0.0001) or found in the lower inner, upper outer or mixed locations (OR = 2.7; P < 0.0001) were also recorded with a better diagnostic possibility compared with other lesions. CONCLUSION: This work identified key features related to diagnostic accuracy of breast cancer on mammograms in a nonscreening population, which is helpful for developing appropriate strategies to improve breast cancer detectability of radiologists.

Master and Apprentice or a Slave to Technology? A Randomized Controlled Trial of Minimal Access Surgery Simulation-Based Training Techniques.

Introduction: This study set out to assess the efficacy of three different approaches to simulation-based minimal access surgery (MAS) training using a three-dimensional printed neonatal thoracoscopic simulator and a virtual simulator. Materials and Methods: Randomized controlled trial of medical students (N = 32), as novices to MAS. The participants performed two construct validated tasks on a thoracoscopic simulator and were then randomly allocated into four intervention groups: (1) three consultant-led sessions on a thoracoscopic simulator; (2) three self-directed learning sessions on the same simulator; (3) self-directed "virtual training" on the "SimuSurg" application; and (4) control. Postintervention participants repeated both tasks. Videos of all task attempts were de-identified and marked by a blinded consultant pediatric surgeon. Results: There were no statistically significant differences in baseline objective structured assessment of technical skills (OSATS) scores or demographics in any group. For the "ring transfer" task, Groups 1 and 2 showed significant improvement after intervention, with no significant change in Groups 3 or 4. There was no significant difference between Groups 1 or 2 in postintervention scores. For the "needle pass" task, no group demonstrated a statistically significant improvement after intervention. Conclusion: Practice on a physical simulator either consultant-led or self-directed led to improved scores for MAS novices compared with a virtual simulator or no intervention for a simple "ring transfer" task. This suggests that time on the physical simulator was the most important factor and implies that trainees could usefully practice simple tasks at their convenience rather than require consultant supervision. This improvement is not seen in more challenging tasks such as the "needle pass."

Development of an instrumented thoracoscopic surgical trainer for objective evaluation of esophageal atresia/tracheoesophageal fistula repair.

Operative repair of complex conditions such as esophageal atresia and tracheoesophageal fistula (EA/TEF) is technically demanding, but few training opportunities exist outside the operating theater for surgeons to attain these skills. Learning them during surgery on actual neonates where the stakes are high, margins for error narrow, and where outcomes are influenced by technical expertise, is problematic. There is an increasing demand for high-fidelity simulation that can objectively measure performance. We developed such a simulator to measure force and motion reliably, allowing quantitative feedback of technical skill. A 3D-printed simulator for thoracoscopic repair of EA/TEF was instrumented with motion and force tracking components. A 3D mouse, inertial measurement unit (IMU), and optical sensor that captured force and motion data in four degrees of freedom (DOF) were calibrated and verified for accuracy. The 3D mouse had low average relative errors of 2.81%, 3.15%, and 6.15% for 0 mm, 10 mm offset in Y, and 10 mm offset in X, respectively. This increased to - 23.5% at an offset of 42 mm. The optical sensors and IMU displayed high precision and accuracy with low SDs and average relative errors, respectively. These parameters can be a useful measurement of performance for thoracoscopic EA/TEF simulation prior to surgery. Graphical abstract Inclusion of sensors into a high-fidelity simulator design can produce quantitative feedback which can be used to objectively asses performance of a technically difficult procedure. As a result, more surgical training can be done prior to operating on actual patients in the operating theater.

Drug-Free Approach To Study the Unusual Cell Cycle of Giardia intestinalis.

Giardia intestinalis is a protozoan parasite that causes giardiasis, a form of severe and infectious diarrhea. Despite the importance of the cell cycle in the control of proliferation and differentiation during a giardia infection, it has been difficult to study this process due to the absence of a synchronization procedure that would not induce cellular damage resulting in artifacts. We utilized counterflow centrifugal elutriation (CCE), a size-based separation technique, to successfully obtain fractions of giardia cultures enriched in G1, S, and G2. Unlike drug-induced synchronization of giardia cultures, CCE did not induce double-stranded DNA damage or endoreplication. We observed increases in the appearance and size of the median body in the cells from elutriation fractions corresponding to the progression of the cell cycle from early G1 to late G2. Consequently, CCE could be used to examine the dynamics of the median body and other structures and organelles in the giardia cell cycle. For the cell cycle gene expression studies, the actin-related gene was identified by the program geNorm as the most suitable normalizer for reverse transcription-quantitative PCR (RT-qPCR) analysis of the CCE samples. Ten of 11 suspected cell cycle-regulated genes in the CCE fractions have expression profiles in giardia that resemble those of higher eukaryotes. However, the RNA levels of these genes during the cell cycle differ less than 4-fold to 5-fold, which might indicate that large changes in gene expression are not required by giardia to regulate the cell cycle. IMPORTANCE Giardias are among the most commonly reported intestinal protozoa in the world, with infections seen in humans and over 40 species of animals. The life cycle of giardia alternates between the motile trophozoite and the infectious cyst. The regulation of the cell cycle controls the proliferation of giardia trophozoites during an active infection and contains the restriction point for the differentiation of trophozoite to cyst. Here, we developed counterflow centrifugal elutriation as a drug-free method to obtain fractions of giardia cultures enriched in cells from the G1, S, and G2 stages of the cell cycle. Analysis of these fractions showed that the cells do not show side effects associated with the drugs used for synchronization of giardia cultures. Therefore, counterflow centrifugal elutriation would advance studies on key regulatory events during the giardia cell cycle and identify potential drug targets to block giardia proliferation and transmission.

Chronic tarsal conjunctivitis.

BACKGROUND: Toxicity is rarely considered in the differential diagnosis of conjunctivitis, but we present here a new form of toxic conjunctivitis with unusual clinical features. Between 2010 and 2013, a new clinical presentation of chronic conjunctivitis unresponsive to normal treatment was noted within a Primary Care Ophthalmology Service. METHODS: Retrospective review of case records and histopathology results. RESULTS: A total of 55 adult patients, all females, presented with epiphora and stickiness. They did not complain of itch and had had symptoms for an average of 9 months. Clinical examination showed bilateral moderate to severe upper and lower tarsal conjunctival papillary reaction, without corneal or eyelid changes and mild bulbar conjunctival hyperaemia in a third of cases. Biopsies were taken in 15 cases to exclude an atypical infection or lymphoma. Histologically, there was a variable superficial stromal lymphocytic infiltrate, involving the epithelium in more severe cases. The majority of the cells were CD3 positive T-lymphocytes and follicle formation was not noted. The clinical history in all cases included prolonged use of eye make- up and other facial cosmetic products. Clinical symptoms of epiphora settled with topical steroid drops, but the clinical signs of chronic tarsal inflammation persisted until withdrawal of the facial wipes thought to contain the inciting agent, though the exact nature of this remains unclear. CONCLUSION: The presentation, appearances, histological features are consistent with a contact allergen-driven chronic conjunctivitis. Steroid treatment provided good relief of symptoms and patients were advised to avoid potential contact allergens. Management remains difficult. Further research into contact allergies of mucous membranes and identification of its allergens is required.

A case series of rapid prototyping and intraoperative imaging in orbital reconstruction.

In Christchurch Hospital, rapid prototyping (RP) and intraoperative imaging are the standard of care in orbital trauma and has been used since February 2013. RP allows the fabrication of an anatomical model to visualize complex anatomical structures which is dimensionally accurate and cost effective. This assists diagnosis, planning, and preoperative implant adaptation for orbital reconstruction. Intraoperative imaging involves a computed tomography scan during surgery to evaluate surgical implants and restored anatomy and allows the clinician to correct errors in implant positioning that may occur during the same procedure. This article aims to demonstrate the potential clinical and cost saving benefits when both these technologies are used in orbital reconstruction which minimize the need for revision surgery.

Leptin promotes glioblastoma.

The hormone leptin has a variety of functions. Originally known for its role in satiety and weight loss, leptin more recently has been shown to augment tumor growth in a variety of cancers. Within gliomas, there is a correlation between tumor grade and tumor expression of leptin and its receptor. This suggests that autocrine signaling within the tumor microenvironment may promote the growth of high-grade gliomas. Leptin does this through stimulation of cellular pathways that are also advantageous for tumor growth and recurrence: antiapoptosis, proliferation, angiogenesis, and migration. Conversely, a loss of leptin expression attenuates tumor growth. In animal models of colon cancer and melanoma, a decline in the expression and secretion of leptin resulted in a reduction of tumor growth. In these models, positive mental stimulation through environmental enrichment decreased leptin secretion and improved tumor outcome. This review explores the link between leptin and glioblastoma.