The effect of body mass index on the outcomes of cementless medial mobile-bearing unicompartmental knee replacements.

PURPOSE: Given an increasingly overweight population, unicompartmental knee replacements (UKRs) are being performed in patients with higher body mass indices (BMIs). There are concerns that cemented fixation will not last. Cementless fixation may offer a solution, but the long term results in different BMI groups has not been assessed. We studied the effect of BMI on the outcomes of cementless UKRs. METHODS: A prospective cohort of 1000 medial cementless mobile-bearing UKR with a mean follow up of 6.6 years (SD 2.7) were analysed. UKRs were categorised into four BMI groups: (1) ≥ 18.5 to < 25 kg/m2 (normal), (2) 25 to < 30 kg/m2 (overweight), (3) 30 to < 35 kg/m2 (obese class 1) and (4) ≥ 35 kg/m2 (obese class 2). Implant survival was assessed using endpoints reoperation and revision. Functional outcomes were assessed. RESULTS: Ten-year cumulative revision rate for the normal (n = 186), overweight (n = 434), obese class 1 (n = 213) and obese class 2 (n = 127) groups were 1.8% (CI 0.4-7.4), 2.6% (CI 1.3-5.1), 3.8% (CI 1.5-9.2) and 1.7% (CI 0.4-6.8) with no significant differences between groups (p = 0.79). The 10-year cumulative reoperation rates were 2.7% (CI 0.8-8.2), 3.8% (CI 2.2-6.6), 5.2% (CI 2.5-10.7) and 1.7% (CI 0.4-6.8) with no significant differences between groups (p = 0.44). The 10-year median Oxford Knee Score were 43.0, 46.0, 44.0 and 38.0 respectively. CONCLUSION: Cementless mobile-bearing UKR has low 10-year reoperation and revision rates across in all BMI groups, and there are no significant differences between the groups. Although higher BMI groups had slightly worse functional outcomes, the improvement in function compared to preoperatively  tended to be better. This study suggests that BMI should not be considered a contraindication for the cementless mobile-bearing UKR.

Do age, gender, and region affect tibial slope? A multi-center study.

INTRODUCTION: Tibial slope is a parameter that is important to recognize in knee kinematics and knee surgery. A very wide range of values governing posterior tibial slope exist in the literature. This study is based on the hypothesis that age, gender and region may have an effect on the tibial slope. MATERIALS AND METHODS: A total of 1800 lateral knee radiographies from five different countries [Turkey, Germany, Italy, Spain, and the United Kingdom (UK)] were utilized to measure the native posterior tibial slope. Participants were categorized in deciles with each decade of age after 40 years determined as a separate age group. Accordingly, four different age categories were formed in total, namely, the 40- to 49-, 50- to 59-, 60-69, and 70- to 79-year-old groups. Patients with severe knee osteoarthritis, those with a history of arthroscopic and open surgery around the knee, and those with severe morbid obesity and those outside the specified age group were excluded from the study. The angle between the line tangential to the medial tibial plateau and the proximal anatomical axis of the tibia was measured. RESULTS: The tibial slope values of both males and females in the Turkish population were found to be higher than those in other populations. It was observed that tibial slope values increased with age in females in all populations, except for those in the Spanish and UK populations. In the male population, it was found that tibial slope values increased with age in all populations except in the Spanish population. CONCLUSIONS: Region, age, and gender affect tibial slope in different populations in various ways. Our study shows that the region an individual lives in and living conditions affect the tibial slope.

Highly Tunable Beyond-Room-Temperature Intrinsic Ferromagnetism in Cr-Doped Topological Crystalline Insulator SnTe Crystals.

The combination of topological phase and intrinsic beyond-room-temperature ferromagnetism is expected to realize the quantum anomalous Hall effect at a high temperature. However, no beyond-room-temperature intrinsic ferromagnetism has been reported in either topological insulator or topological crystalline insulator (TCI) so far. Here, we report Cr-doping in TCI-phase SnTe crystals which possess highly tunable beyond-room-temperature intrinsic ferromagnetism including Tc, magnetic moment, and coercivity by varying Cr contents and crystal thickness. With the increase of the Cr content, the Tc increases by 159 K from 221 to 380 K and the saturation magnetic moments increase by ∼23.6 times from 0.018 to 0.421 µB/f.u. This intrinsic beyond-room-temperature ferromagnetism is fully demonstrated by the anomalous Hall effect and magneto-optical Kerr effect in a single CrxSn1-xTe nanosheet. Moreover, the room-temperature tunneling magnetoresistance effect has been realized by using a CrxSn1-xTe flake, a Fe thin film, and a commercially compatible ultrathin AlOx tunneling barrier. This work indicates a great potential of CrxSn1-xTe crystals in room-temperature magnetoelectronic and spintronic devices.

The effect of age on the outcomes of cementless mobile bearing unicompartmental knee replacements.

PURPOSE: Unicompartmental Knee Replacements (UKR) are being performed in patients with increasing demands and life expectancies with surgical concerns that cemented fixation will not last. Cementless fixation may offer a solution, but the results in different age groups have not been assessed. The effect of age at surgery on the outcomes of cementless UKRs was investigated. METHODS: A prospective cohort of 1000 medial cementless mobile bearing UKR were analysed. Patients were categorised into four age groups (< 55, 55 to < 65, 65 to < 75 and ≥ 75 years). Implant survival was assessed using endpoints reoperation, revision and major revision requiring revision knee replacement components. Functional outcomes were assessed. RESULTS: 10 year cumulative revision rate for the < 55, 55 to < 65, 65 to < 75 and ≥ 75 groups were 2.1% (CI 0.6-6.1), 1.8% (CI 0.6-5.3), 3.2% (CI 1.5-6.5) and 4.1% (1.7-9.6) with no differences between groups (p = 0.52). Two of the 22 revisions were considered major. The 10 year cumulative reoperation rates were 4.5% (CI 2.0-10.0), 3.0% (CI 1.3-6.5), 3.8% (CI 2.0-7.1) and 4.1% (CI 1.7-9.6) with no differences between groups (p = 0.81). The 10 year median Oxford Knee Scores were 42.5, 46.5, 45 and 42.5, respectively. The 10 year median Objective American Knee Society Scores were 95 for all age groups. CONCLUSION: The cementless mobile bearing UKR has low reoperation and revision rates and similar functional outcomes in all age groups. Cementless UKR should be used in all age groups and age should not be considered a contraindication. LEVEL OF EVIDENCE: III.

Acceptable outcomes with unicompartmental knee replacement and PCL deficiency are achievable: a case series of nine patients.

PURPOSE: Posterior cruciate ligament (PCL) deficiency is considered to be a contraindication for unicompartmental knee replacement (UKR); however, there is no evidence to support or contradict this. There are occasional circumstances where UKR in PCL deficient patients have been performed where the patient otherwise satisfies the indications for UKR. The aim of this paper is to describe the outcome of UKR in PCL deficient patients. METHODS: A retrospective study of patients with painful medial compartment osteoarthritis and PCL deficiency treated with Oxford UKR between 2006 and 2015 was undertaken. Clinical records from a prospectively recorded database were reviewed and outcomes were assessed based on revision rate, Oxford Knee Score (OKS), American Knee Society score and Tegner Activity Score. RESULTS: Nine patients were identified. The median age at surgery was 51 years (range 42-80) and median follow-up was 6 years (range 1-10). There was one bearing dislocation requiring open exchange. The outcome of seven patients was excellent (OKS > 41). Two patients, who were both elderly, had good outcomes (OKS 41 and 39). One patient had a poor outcome, but it is not clear if this was related to the knee as she had a learning disability and examination and radiographs of the knee were satisfactory. CONCLUSION: The results of this small series suggest that excellent results can be achieved with UKR for selected patients with medial osteoarthritis in a PCL deficient knee that was functioning well before the osteoarthritis developed. On the basis of this a larger study should be undertaken. Until more results are available PCL deficiency should be considered a relative contra-indication to UKR. LEVEL OF EVIDENCE: IV.

Cytochrome c oxidase dysfunction enhances phagocytic function and osteoclast formation in macrophages.

The mitochondria-to-nucleus retrograde signaling (MtRS) pathway aids in cellular adaptation to stress. We earlier reported that the Ca2+- and calcineurin-dependent MtRS induces macrophage differentiation to bone-resorbing osteoclasts. However, mechanisms through which macrophages sense and respond to cellular stress remain unclear. Here, we induced mitochondrial stress in macrophages by knockdown (KD) of subunits IVi1 or Vb of cytochrome c oxidase (CcO). Whereas both IVi1 and Vb KD impair CcO activity, IVi1 KD cells produced higher levels of cellular and mitochondrial reactive oxygen species with increased glycolysis. Additionally, IVi1 KD induced the activation of MtRS factors NF-κB, NFAT2, and C/EBPδ as well as inflammatory cytokines, NOS 2, increased phagocytic activity, and a greater osteoclast differentiation potential at suboptimal RANK-L concentrations. The osteoclastogenesis in IVi1 KD cells was reversed fully with an IL-6 inhibitor LMT-28, whereas there was minimal rescue of the enhanced phagocytosis in these cells. In agreement with our findings in cultured macrophages, primary bone marrow-derived macrophages from MPV17-/- mice, a model for mitochondrial dysfunction, also showed higher propensity for osteoclast formation. This is the first report showing that CcO dysfunction affects inflammatory pathways, phagocytic function, and osteoclastogenesis.-Angireddy, R., Kazmi, H. R., Srinivasan, S., Sun, L., Iqbal, J., Fuchs, S. Y., Guha, M., Kijima, T., Yuen, T., Zaidi, M., Avadhani, N. G. Cytochrome c oxidase dysfunction enhances phagocytic function and osteoclast formation in macrophages.

Endoscopic suturing for the prevention of stent migration in benign upper gastrointestinal conditions: a comparative multicenter study.

BACKGROUND AND STUDY AIMS: Fully covered self-expandable metal stents (FCSEMSs) have increasingly been used in benign upper gastrointestinal (UGI) conditions; however, stent migration remains a major limitation. Endoscopic suture fixation (ESF) may prevent stent migration. The aims of this study were to compare the frequency of stent migration in patients who received endoscopic suturing for stent fixation (ESF group) compared with those who did not (NSF group) and to assess the impact of ESF on clinical outcome. PATIENTS AND METHODS: This was a retrospective study of patients who underwent FCSEMS placement for benign UGI diseases. Patients were divided into either the NSF or ESF group. Outcome variables, including stent migration, clinical success (resolution of underlying pathology), and adverse events, were compared. RESULTS: A total of 125 patients (44 in ESF group, 81 in NSF group; 56 benign strictures, 69 leaks/fistulas/perforations) underwent 224 stenting procedures. Stent migration was significantly more common in the NSF group (33 % vs. 16 %; P = 0.03). Time to stent migration was longer in the ESF group (P = 0.02). ESF appeared to protect against stent migration in patients with a history of stent migration (adjusted odds ratio [OR] 0.09; P = 0.002). ESF was also significantly associated with a higher rate of clinical success (60 % vs. 38 %; P = 0.03). Rates of adverse events were similar between the two groups. CONCLUSIONS: Endoscopic suturing for stent fixation is safe and associated with a decreased migration rate, particularly in patients with a prior history of stent migration. It may also improve clinical response, likely because of the reduction in stent migration.

Age, sex and the association between skin test responses and IgE titres with asthma.

BACKGROUND: Skin prick tests (SPTs) and allergen-specific serum IgE (sIgE) measurements are the main diagnostic tools for confirming atopic sensitization. Results are usually reported as 'positive' or 'negative', using the same arbitrary cut-offs (SPT>3 mm, sIgE>0.35 kUA /l) across different ages and sexes. We investigated the influence of age and sex on the interpretation of allergy test in the context of childhood asthma. METHODS: In a population-based birth cohort (n = 1051), we ascertained the information on asthma/wheeze (validated questionnaires) and performed SPTs and sIgE measurement to inhalant allergens (dust mite, cat, dog) at follow-ups between ages three and 11 years. We investigated the association between quantitative sensitization (sum of SPT mean wheal diameters [MWD] and sIgE titres to the three allergens) and current wheeze and asthma across ages and sexes. RESULTS: We observed a significant association between the SPT MWD and sIgE titres and wheeze/asthma at most ages and for both sexes. However, the strength of this association was age- and sex-dependent. For SPTs, the strength of the association between MWD and asthma increased with increasing age; we observed the opposite pattern for sIgE titre. For any given SPT MWD/sIgE titre, boys were significantly more likely to express clinical symptoms, particularly in early life; this difference between males and females diminished with age and was no longer significant by age 11 years. CONCLUSIONS: Age and sex should be taken into account when interpreting the results of skin tests and sIgE measurement, and age- and sex-specific normative data are needed for these allergy tests.

Clinical Outcomes, Efficacy, and Adverse Events in Patients Undergoing Esophageal Stent Placement for Benign Indications: A Large Multicenter Study.

INTRODUCTION: Esophageal stents are commonly used to treat benign esophageal conditions including refractory benign esophageal strictures, anastomotic strictures, fistulae, perforations and anastomotic leaks. Data on outcomes in these settings remain limited. METHODS: We performed a retrospective multicenter study of patients who underwent fully or partially covered self-expandable stent placement for benign esophageal diseases. Esophageal stent placements were performed for the following indications: (1) benign refractory esophageal strictures, (2) surgical anastomotic strictures, (3) esophageal perforations, (4) esophageal fistulae, and (5) surgical anastomotic leaks. RESULTS: A total of 70 patients underwent esophageal stent placement for benign esophageal conditions. A total of 114 separate procedures were performed. The most common indication for esophageal stent placement was refractory benign esophageal stricture (48.2%). Global treatment success rate was 55.7%. Treatment success rate was 33.3% in refractory benign strictures, 23.1% in anastomotic strictures, 100% in perforations, 71.4% in fistulae, and 80% in anastomotic leaks. Stent migration was noted in 28 of 70 patients (40%), most commonly seen in refractory benign strictures. CONCLUSIONS: This is one of the largest studies to date of esophageal stents to treat benign esophageal diseases. Success rates are lowest in benign esophageal strictures. These patients have few other options beyond chronic dilations, feeding tubes, and surgery, and fully covered self-expandable metallic stent give patients a chance to have their problem fixed endoscopically and still eat by mouth. Perforations, fistulas, and leaks respond very well to esophageal stenting, and stenting should be considered as a first-line therapy in these settings.

Urgent referral for suspected CNS cancer: which clinical features are associated with a positive predictive value of 3 % or more?

BACKGROUND: Urgent referral for suspected central nervous system (CNS) cancer is recommended, but little analysis of the referral criteria diagnostic performance has been conducted. New 2015 NICE guidance recommends direct brain imaging for patients with symptoms with positive predictive values (PPV) of 3 %, but further guidance is needed. METHODS: A 12-month retrospective evaluation of 393 patients referred under previous 2005 NICE 2-week rule criteria was conducted. Analysis was based on the three groups of symptoms forming the referral criteria, (1) CNS symptoms, (2) recent onset headaches, (3) rapidly progressive subacute focal deficit/cognitive/behavioural/personality change. Comparison was made with neuroimaging findings. RESULTS: Twelve (3.1 %) of 383 patients who attended clinic had CNS cancer suggesting the combination of clinical judgement and application of 2005 criteria matched the 2015 guideline's PPV threshold. PPVs for the three groups of symptoms were (1) 4.1 % (95 % CIs 2.0 to 7.4 %), (2) 1.2 % (0.1 to 4.3 %) and (3) 3.7 % (0.1 to 19.0 %). Sensitivities were (1) 83.3 % (95 % CIs 51.6 to 97.9 %), (2) 16.7 % (2.1 to 48.4 %), and (3) 8.3 % (0.2 to 38.5 %); specificities were (1) 37.2 % (32.3 to 42.3 %), (2) 55.5 % (50.3 to 60.7 %) and (3) 93.0 % (89.9 to 95.4 %). Of 288 patients who underwent neuroimaging, 59 (20.5 %) had incidental findings, most commonly cerebrovascular disease. CONCLUSIONS: The 2015 guidance is less prescriptive than previous criteria making clinical judgement more important. CNS symptoms had greatest sensitivity, while PPVs for CNS symptoms and rapidly progressive subacute deficit/cognitive/behavioural/personality change were closest to 3 %. Recent onset headaches had the lowest sensitivity and PPV.

Polymorphism and Expression Profile of Cholecystokinin Type A Receptor in Relation to Gallstone Disease Susceptibility.

In the present study, we investigated expression pattern of Cholecystokinin type A receptor (CCKAR) in relation to its commonly studied polymorphism (rs1800857, T/C) in gallstone disease (GSD) patients and controls. A total of 502 subjects (272 GSD and 230 controls) were enrolled, and genotyping was performed by evaluating restriction fragments of PstI digested DNA. For analyzing expression pattern of CCKAR in relation to polymorphism, gallbladder tissue samples from 80 subjects (GSD-55; control-25) were studied. Expression of CCKAR mRNA was evaluated by reverse transcriptase-PCR and confirmed using real-time PCR. Protein expression was evaluated by enzyme-linked immunosorbent assay. We observed significantly (p < 0.0001) lower expression of CCKAR mRNA and protein in GSD tissues as compared with control. Significantly higher frequency of A1/A1 genotype (C/T transition) (p = 0.0005) was observed for GSD as compared with control. Expression of CCKAR protein was found to be significantly lower (p < 0.0001) in A1/A1 genotype as compared with other genotypes for GSD patients. Perhaps, this is the first report providing evidence of alteration in CCKAR expression in relation to its polymorphism elucidating the molecular pathway of the disease. Additional investigations with lager sample size are needed to confirm these findings.

Prognostic significance of survivin in resected gallbladder cancer.

BACKGROUND: Survivin, a novel inhibitor of apoptosis, plays a role in oncogenesis and has been correlated with poor prognosis. We investigated its expression in gallbladder tissues of control, cholelithiasis, and gallbladder cancer (GBC). Survivin expression was correlated with different clinicopathologic parameters including prognosis in patients with GBC. MATERIALS AND METHODS: Gallbladder tissue samples were collected from GBC (n = 39), cholelithiasis (n = 30), and control (n = 25). Expression of survivin messenger RNA (mRNA) was evaluated by real time polymerase chain reaction. Protein quantification was done by enzyme-linked immunosorbent assay. RESULTS: Significantly higher expression of survivin mRNA was observed in GBC (2.9-fold) and cholelithiasis (1.85-fold) as compared with control (P < 0.0001). In GBC, increased survivin expression (mRNA and protein) was significantly associated with higher tumor stage (stage III versus stage II) (P < 0.0001) and poor tumor differentiation (poor and moderate versus well) (P < 0.0001). No significant correlation was observed with any of the other clinicopathologic factors studied. Increased expression of survivin was associated with shorter survival (median survival 11.5 mo versus 18 mo). CONCLUSIONS: Differential expression of survivin in GBC suggests its possible role in gallbladder carcinogenesis. Its overexpression is associated with poor prognosis. Assessment of survivin might be used to stratify GBC patients for optimal treatment modalities, including targeted therapy.

Expression of survivin mRNA in gallbladder cancer: a diagnostic and prognostic marker?

Survivin, an inhibitor of apoptosis, has been shown to be expressed in various malignancies. However, its role in gallbladder cancer (GBC) has not been evaluated yet. We investigated its expression in peripheral blood of patients with gallbladder diseases (gallstone disease (GSD), n = 30; GBC, n = 39) and compared with healthy controls (n = 25). Survivin expression was correlated with clinicopathological parameters, diagnosis, and prognosis of patients with GBC. Expression of survivin messenger RNA (mRNA) in blood was evaluated by real-time PCR. Significantly higher (P < 0.0001) expression of survivin mRNA was observed in GBC (2.2-fold) and GSD (1.52-fold) as compared to control. In GBC, increased survivin expression was significantly associated with higher tumor stage (stage III vs. stage II; P < 0.0001) and tumor differentiation (poor and moderate vs. well differentiated; P < 0.0001). No significant correlation was observed with any of the other clinicopathological parameters (age, gender, and presence or absence of gallstones) studied. Cutoff value of survivin mRNA relative quantification (RQ) was 1.08, with a sensitivity of 98.55 % and specificity of 100 % for the diseased group (GSD or GBC). RQ value of 1.71 differentiated GBC from GSD with a sensitivity of 89.74 % and specificity of 100 %. Increased expression of survivin was associated with a shorter median overall survival (12 vs. 18 months) in GBC patients. Differential expression of survivin in GBC suggests its possible role and association with poor prognosis. Expression of survivin in peripheral blood could be useful both in the diagnosis and prognosis of GBC.

Prognostic significance of K-ras codon 12 mutation in patients with resected gallbladder cancer.

BACKGROUND: Point mutation of K-ras is associated with carcinogenesis and overall survival in various cancers. We investigated the mutational spectrum of K-ras codon 12 in resected normal and gallbladder cancer tissue samples in a Northern Indian population and correlated it with different clinicopathological parameters. PATIENTS AND METHODS: Gallbladder tissues from normal (n = 24) and cancer patients (n = 39) were analyzed for K-ras codon 12 mutation by restriction fragment length polymorphism. Statistical analysis was carried out using the χ(2) test or Fisher's exact test. Survival was estimated using the Kaplan-Meier method, and the difference between survival curves was analyzed by the log-rank test. RESULTS: The frequency of K-ras mutation was significantly higher (p = 0.001) in gallbladder cancer tissue samples (16/39) compared to normal samples (1/24). Patients with K-ras mutation had a significantly decreased overall survival (p = 0.003), particularly for stage II (p = 0.021) and III (p = 0.009) cancers. No significant correlation was observed with any of the other clinicopathological factors studied. CONCLUSIONS: Gallbladder cancer has a high frequency of K-ras codon 12 mutation with poorer outcomes in resected stage II and III disease. K-ras mutational analysis has important prognostic implications that need to be investigated further.

On the dynamic reconfigurable implementations of MISTY1 and KASUMI block ciphers.

Novel hardware architectures for dynamic reconfigurable implementation of 64-bit MISTY1 and KASUMI block ciphers are proposed to enhance the performance of cryptographic chips for secure IoT applications. The SRL32 primitive (Reconfigurable Look up Tables-RLUTs) and DPR (Dynamic Partial Reconfiguration) are employed to reconfigure single round MISTY1 / KASUMI algorithms on the run-time. The RLUT based architecture attains dynamic logic functionality without extra hardware resources by internally modifying the LUT contents. The proposed adaptive reconfiguration can be adopted as a productive countermeasure against malicious attacks with the added advantage of less reconfiguration time (RT). On the other hand, the block architecture reconfigures the core hardware by externally uploading the partial bit stream and has significant advantages in terms of low area implementation and power reduction. Implementation was carried out on FPGA, Xilinx Virtex 7. The results showed remarkable results with very low area of 668 / 514 CLB slices consuming 460 / 354 mW for RLUT and DPR architectures respectively. Moreover, the throughput obtained for RLUT architecture was found as 364 Mbps with very less RT of 445 nsec while DPR architecture achieved speed of 176 Mbps with RT of 1.1 msec. The novel architectures outperform the stand-alone existing hardware designs of MISTY1 and KASUMI implementations by adding the dynamic reconfigurability while at the same achieving high performance in terms of area and throughput. Design details of proposed unified architectures and comprehensive analysis is described.

The effect of activity on the outcome of cementless mobile bearing unicompartmental knee replacements.

BACKGROUND: Many surgeons consider high activity levels a contraindication to Unicompartmental Knee Replacement (UKR). Cementless fixation is of particular concern given the lack of cement to augment primary stability. We assessed the effect of pre and post-operative activity levels on the outcomes of cementless UKRs. METHODS: A prospective cohort of 1000 medial cementless mobile bearing UKR were analysed. Patients were categorised by their pre-operative and highest post-operative Tegner Activity Score (TAS) and results compared between groups. Outcomes of interest included implant survival, Oxford Knee Score (OKS) and the American Knee Society Score - Objective/Functional (AKSS-O/F). RESULTS: Increasing post-operative activity were not associated with higher revision rates. The 10-year survival of the high activity group (TAS ≥ 5, 96.7% (CI 91.3-98.8), and low/medium activity group (TAS ≤ 4, 98.1% (CI 96.5-99.0)) were not significantly different (p = 0.57). The mean 10-year OKS of the high activity group (46.5, SD 3.1) was significantly (p < 0.001) higher than that of the low/medium activity group (41.3, SD 7.7). There was a significant trend for increasing activity being associated with increasing AKSS-F at 5-years (p < 0.001) and 10 years (p = 0.01) and increasing AKSS-O at 5 years (p < 0.001). Higher pre-operative activity did not significantly increase revision rates and resulted in significantly higher 5-year post-operative scores. CONCLUSIONS: Neither higher pre-operative nor post-operative activity were associated with increased revision rates, but both were associated with better post-operative function. Therefore activity should not be considered a contraindication to cementless mobile bearing UKR and not be restricted post-operatively.

Heterodimerization of cholecystokinin 1 and cholecystokinin 2 receptors in gallbladder cancer: a new mechanism for carcinogenesis.

PURPOSE: Cholecystokinin is present in abundance in gallbladder tissue and mediates function through two structurally related receptors, CCK1R and CCK2R. Heterodimerization of these receptors is known to impact cell growth in vitro. However, the significance of these heterodimers in gallbladder carcinogenesis is relatively unknown. METHODS: Therefore, we evaluated the expression and the dimerization status of CCK1 and CCK2 receptors in human gallbladder carcinoma cell line (GBC-SD) and resected gallbladder tissue from normal (n = 10), cholelithiasis (n = 25) and gallbladder cancer (n = 25) by immunofluorescence/immunohistochemistry and western blot. The dimerization status of CCK1R and CCK2R was evaluated by co-immunoprecipitation. To understand the effect of heterodimerization of these receptors on growth-related signaling pathways, the expression of p-AKT, rictor, raptor and p-ERK was evaluated by western blot. RESULTS: We demonstrated the expression and heterodimerization of CCK1 and CCK2 receptor in GBC-SD gall bladder carcinoma cell line. Knockdown of CCK1R and CCK2R in the cell line led to significant reduction in p-AKT (P = 0.005; P = 0.0001) and rictor (P < 0.001; P < 0.001) levels. In tissue samples, significantly higher expression of CCK1R and CCK2R was observed in gallbladder cancer when compared to other groups both by immunohistochemistry (P = 0.008 and P = 0.013) and western blot (P = 0.009 and P = 0.003). An increase in heterodimer formation of CCK1R with CCK2R was observed in gallbladder cancer when compared to normal and cholelithiasis tissues. No significant difference in the expression of p-AKT and p-ERK was observed between the three groups. CONCLUSION: Our results provide the first evidence of heterodimerization of CCK1R and CCK2R in gallbladder tissue, and its association with development of gallbladder cancer. This finding has potential clinical and therapeutic significance.

Pyo-pericardium secondary to bacteremia in intra-venous drug user.

Pyo-pericardium is a collection of purulent fluid in the pericardial sac. It is a rare finding seen in less than 1% of patients who develop acute pericarditis. The condition, though uncommon, has a mortality risk of 100% in untreated patients and 40% in treated patients. Most of the reported cases in the literature describe the occurrence of pyo-pericardium in IV drug users that's secondary to needle fragment embolization to the pericardium diagnosed through an echocardiogram and CT scan with no evidence of bacteremia. Unlike reported cases, we present a case of pyo-pericardium in a 37-year-old woman with bacteremia from a wound infection on her leg secondary to IV drug use. Needle embolization was ruled out in our case as no foreign object was identified on echocardiography or CT scan. Prompt identification followed by aggressive treatment with pericardial window and systemic antibiotics is crucial for decreasing mortality in such high-risk patients.

Interferon-gamma signaling promotes melanoma progression and metastasis.

Interferon-gamma (IFNG) has long been regarded as the flag-bearer for the anti-cancer immunosurveillance mechanisms. However, relatively recent studies have suggested a dual role of IFNG, albeit there is no direct experimental evidence for its potential pro-tumor functions. Here we provide in vivo evidence that treatment of mouse melanoma cell lines with Ifng enhances their tumorigenicity and metastasis in lung colonization allograft assays performed in immunocompetent syngeneic host mice, but not in immunocompromised host mice. We also show that this enhancement is dependent on downstream signaling via Stat1 but not Stat3, suggesting an oncogenic function of Stat1 in melanoma. The experimental results suggest that melanoma cell-specific Ifng signaling modulates the tumor microenvironment and its pro-tumorigenic effects are partially dependent on the γδ T cells, as Ifng-enhanced tumorigenesis was inhibited in the TCR-δ knockout mice. Overall, these results show that Ifng signaling may have tumor-promoting effects in melanoma by modulating the immune cell composition of the tumor microenvironment.

Nano-scale charge trapping memory based on two-dimensional conjugated microporous polymer.

There is a growing interest in new semiconductor nanostructures for future high-density high-performance flexible electronic devices. Two-dimensional conjugated microporous polymers (2D-CMPs) are promising candidates because of their inherent optoelectronic properties. Here, we are reporting a novel donor-acceptor type 2D-CMP based on Pyrene and Isoindigo (PI) for a potential nano-scale charge-trapping memory application. We exfoliated the PI polymer into ~ 2.5 nm thick nanoparticles (NPs) and fabricated a Metal-Insulator-Semiconductor (MIS) device with PI-NPs embedded in the insulator. Conductive AFM (cAFM) is used to examine the confinement mechanism as well as the local charge injection process, where ultrathin high-κ alumina supplied the energy barrier for confining the charge carrier transport. We have achieved a reproducible on-and-off state and a wide memory window (ΔV) of 1.5 V at a relatively small reading current. The device displays a low operation voltage (V < 1 V), with good retention (104 s), and endurance (103 cycles). Furthermore, a theoretical analysis is developed to affirm the measured charge carriers' transport and entrapment mechanisms through and within the fabricated MIS structures. The PI-NPs act as a nanoscale floating gate in the MIS-based memory with deep trapping sites for the charged carriers. Moreover, our results demonstrate that the synthesized 2D-CMP can be promising for future low-power high-density memory applications.