Future of combination therapy with dabrafenib and trametinib in metastatic melanoma

Introduction: Combination therapy with BRAF and MEK inhibitors is a recommended treatment strategy for metastatic melanoma patients with BRAF^V600 mutations. This treatment provides significant response rates and little added toxicity, with relatively improved survival outcomes compared to RAF/MEK inhibitor monotherapy and chemotherapy.

Areas covered: This review covers the pharmacology, efficacy, and toxicity data derived from clinical studies of dabrafenib, trametinib, and the combination thereof. The major downfall of combiDT is the limited durability of response, which is largely due to acquired resistance in the MAPK pathway.

Expert opinion: Future directions of combiDT concentrate on further combinations with immunotherapy or other targeted inhibitors, referred to triple-agent therapy, which may be essential to improving durability of responses and overcoming resistance.     

Functional and chronic anorectal and pelvic pain disorders

Several organic and functional disorders of the urinary bladder, reproductive tract, anorectum, and the pelvic floor musculature cause pelvic pain. This article describes functional disorders in which chronic pelvic and anorectal pain cannot be explained by a structural or other specified pathology. Currently, these functional disorders are classified into urogynecologic conditions or cystitis and painful bladder syndrome, anorectal disorders, and the levator ani syndrome. Although nomenclature suggests that these conditions are distinct, there is considerable overlap of their symptoms and these disorders have much in common.     

Circulating markers of oxidative stress and liver fibrosis in Sudanese subjects at risk of schistosomiasis and hepatitis

Epidemiological studies in the developing world are frequently biased by the simultaneous presence of several infectious pathogens. In the present study, we examined the usefulness of circulating markers of oxidative stress and liver fibrosis to investigate the distinct forms of chronic liver inflammations associated with schistosomiasis and viral hepatitis, respectively. The study was performed in a Sudanese population exposed to Schistosoma. Circulating hyaluronic acid (HA) was used as a marker of liver fibrosis; the severity of schistosomiasis was determined by ultrasonic examination; viral hepatitis infection was ascertained by circulating anti-hepatitis antibodies. Serum markers were examined also in Sudanese subjects not exposed to Schistosoma infection and in French control subjects. We found a drastic decrease of lycopene levels in the subjects exposed to schistosomiasis in comparison with non-exposed Sudanese and French control subjects. Retinol, alpha-tocopherol and five carotenoids were unchanged. Lycopene depletion was unlikely to be due to variations of nutritional origin, since the lycopene/beta-carotene ratio was five-fold lower in the population at risk of schistosomiasis than in the other groups. We found that high HA serum levels were associated with severe periportal fibrosis but not with viral infection. Conversely, levels of the oxidized lipid malondialdehyde (MDA) were associated with viral infection but not with the severity of schistosomiasis, even though the two infections had additive effects. We concluded that serum markers are valuable tools for investigating the complex effects of co-existing factors of chronic liver inflammation.     

Rheumatoid arthritis and anti-thyroid antibodies

The aim of this study was to evaluate the quality of B cell responses in patients with Inflammatory Bowel Disease (IBD) and healthy individuals of different ages, vaccinated with the pandemic (p)2009 influenza vaccine. The in vivo response was measured by the hemagglutination inhibition (HAI) assay, which represents the most established correlate with vaccine protectiveness. The in vitro response was measured by activation-induced cytidine deaminase (AID) in cultures of vaccine-stimulated PBMC. Both responses are somewhat impaired in IBD patients undergoing anti-TNF-α treatment but these are much more decreased in IBD patients undergoing treatment with anti-TNF-α and immunosuppressive (IS) drugs. These latter patients had in vivo and in vitro B cell responses similar to those of elderly individuals. Moreover, as we have previously demonstrated in healthy subjects, the in vitro response to the polyclonal stimulus CpG may be used as a biomarker for subsequent vaccine response and AID activation is correlated with the serum response in IBD patients, as it is in healthy individuals. These results altogether indicate that IBD patients on anti-TNF-α and IS have significantly impaired in vivo and in vitro B cell responses, as compared to those on monotherapy. This is the first report to demonstrate that B cell defects, as measured by the autonomous AID reporter, in IBD patients contribute to reduced humoral responses to the influenza vaccine, as we have previously shown for elderly individuals.     

Immobilization of amyloglucosidase onto macroporous cryogels for continuous glucose production from starch

Poly(methyl methacrylate-glycidyl methacrylate) [Poly(MMA-GMA)] cryogels were synthesized using monomers of methylmethacrylic acid and epoxy group bearing GMA via radical cryopolymerization technique. Synthesized cryogels were used for the immobilization of amyloglucosidase to the cryogel surface using epoxy chemistry. Characterizations of the free and immobilized amyloglucosidase were carried out by comparing the optimum and kinetic parameters of enzymes. For this, pH and temperature profiles of free and immobilized preparation were studied and, it was found that, optimum pH of enzyme was not change upon immobilization (pH 5.0), while optimum temperature of the enzyme shifted 10 °C to warmer region after immobilization (optimum temperatures for free and immobilized enzyme were 55 and 65 °C, respectively). Kinetic parameters of free and immobilized enzyme were also investigated and K_m values of free and immobilized amyloglucosidase were found to be 2.743 and 0.865 mg/mL, respectively. V_max of immobilized amyloglucosidase was found to be (0.496 µmol/min) about four times less than that of free enzyme (2.020 µmol/min). Storage and operational stabilities of immobilized amyloglucosidase were also studied and it was showed that immobilized preparation had much more stability than free preparation. In the present work, amyloglucosidase immobilized poly(MMA-GMA) cryogels were used for continuous glucose syrup production from starch for the first time. Efficiency of immobilized enzyme was investigated and released amount of glucose was found to be 2.54 mg/mL at the end of the 5 min of hydrolysis. The results indicate that the epoxy functionalized cryogels offer a good alternative for amyloglucosidase immobilization applications with increased operational and thermal stability, and reusability. Also, these cryogels can be used for immobilization of other industrially valuable enzymes beyond amyloglucosidase.     

The Role of Serum Procalcitonin Levels in Predicting Ascitic Fluid Infection in Hospitalized Cirrhotic and Non-cirrhotic Patients

Objective: To determine the role of serum procalcitonin levels in predicting ascites infection in hospitalized cirrhotic and non-cirrhotic patients.Methods: A total of 101 patients (mean age: 63.4±1.3, 66.3% were males) hospitalized due to cirrhosis (n=88) or malignancy related (n=13) ascites were included in this study. Spontaneous bacterial peritonitis (SBP, 19.8%), culture-negative SBP (38.6%), bacterascites (4.9%), sterile ascites (23.8%) and malign ascites (12.9%) groups were compared in terms of procalcitonin levels in predicting ascites infection. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic performance of procalcitonin levels and predicting outcome of procalcitonin levels was compared with C-reactive protein (CRP).Results: Culture positivity was determined in 26.7% of overall population. Serum procalcitonin levels were determined to be significantly higher in patients with positive bacterial culture in ascitic fluid compared to patients without culture positivity (median (min-max): 4.1 (0.2-36.4) vs. 0.4 (0.04-15.8), p<0.001). Using ROC analysis, a serum procalcitonin level of <0.61 ng/mL in SBP (area under curve (AUC): 0.981, CI 95%: 0.000-1.000, p<0.001), <0.225 ng/mL in culture-negative SBP (AUC: 0.743, CI 95%: 0.619-0.867, p<0.001), <0.42 ng/mL in SBP and culture-negative SBP patients (AUC: 0.824, CI 95%: 0.732-0.916, p<0.001), and <1.12 ng/mL in bacterascites (AUC: 0.837, CI 95%: 0.000-1.000, p=0.019) were determined to accurately rule out the diagnosis of bacterial peritonitis. Predictive power of serum procalcitonin levels in SBP + culture-negative SBP group (AUCs: 0.824 vs 0.622, p=0.004, Fig 4), culture-positive SBP (AUCs: 0.981 vs 0.777, p=0.006, Fig 5) and (although less powerfull) in culture-negative SBP (AUCs: 0.743 vs 0.543, p=0.02, Fig 6) were found significantly higher than CRP.Conclusion: According to our findings determination of serum procalcitonin levels seems to provide satisfactory diagnostic accuracy in differentiating bacterial infections in hospitalized patients with liver cirrhosis related ascites.     

Optical optimization of double-side-textured monolithic perovskite–silicon tandem solar cells for improved light management

Tandem configuration-containing perovskite and silicon solar cells are promising candidates for realizing a high power conversion efficiency of 30% at reasonable costs. Silicon solar cells with planar front surfaces used in tandem devices cause high optical losses, which significantly affects their efficiency. Moreover, some studies have explored the fabrication of perovskites on textured silicon cells. However, due to improper texturing, light trapping is not ideal in these devices, which reduces the efficiency. In this work, we optimized the pyramid height of textured silicon cells and efficiently characterized them to achieve enhanced light trapping. Two different kinds of perovskites, namely, Cs_0.17FA_0.6Pb(Br_0.17I_0.7)₃ and Cs_0.25FA_0.6Pb(Br_0.20I_0.7)₃ with wide bandgaps were conformally deposited on textured silicon cells, and the performance of these flat and fully textured tandem devices was numerically analyzed. The thickness of each layer in the tandem cell was optimized in a way to ensure a perfect current match between the top perovskite and bottom silicon subcells. The results indicated that the textured tandem configuration enhances light absorption over a broad spectral range due to the optimized pyramid height compared to flat surfaces. Eventually, the photovoltaic parameters of the proposed tandem cell were compared with the already existing structures, and our design supports large values of open circuit voltage (V_oc) = 1.78 V, short circuit current density (J_sc) = 20.09 mA cm⁻², fill factor (FF) = 79.01%, and efficiency (η) = 28.20% compared to other kinds of tandem solar cells.

Tandem configuration-containing perovskite and silicon solar cells are promising candidates for realizing a high power conversion efficiency of 30% at reasonable costs.     

Enzymatic Debridement in Necrotizing Pancreatitis

Multiple organ failure and pancreatic necrosis are the factors that determine prognosis in acute pancreatitis attacks. We investigated the effects of collagenase on the debridement of experimental pancreatic necrosis. The study covered 4 groups; each group had 10 rats. Group I was the necrotizing pancreatitis group. Group II was the collagenase group with pancreatic loge by isotonic irrigation following necrotizing pancreatitis. Group III was the collagenase group with pancreatic loge following necrotizing pancreatitis. Group IV was the intraperitoneal collagenase group following necrotizing pancreatitis. The progress of the groups was compared hematologically and histopathologically. There was no difference among the groups regarding the levels of leukocyte, hemogram, and urea. The differences in AST levels between Group I and II; and differences in glucose, calcium, LDH, AST, and amylase between Group II and III; between Group II and IV; between Group I and III; and between Group I and IV were statistically significant (P < 0.05). There were statistically significant differences between Group II and III, and Group II and IV regarding edema, acinar necrosis, inflammatory cell infiltration, hemorrhage, and fat necrosis (P < 0.05). In conclusion, the collagenase preparation used in this experimental pancreatitis model was found to be effective in the debridement of pancreatic necrosis.Key words: Acute pancreatitis, Necrose, Collagenase, DebridementAcute pancreatitis (AP) is a nonbacterial inflammatory disease of the pancreas that can range from interstitial edema to pancreatic necrosis in its severest form. In about 20% of AP attacks necrosis can develop in the pancreas while the disease limits itself and regresses in a couple of days in many patients (80%).¹The definitions that are still widely in effect today regarding the classification of acute pancreatitis were determined in 1992 at the Atlanta Conference.² The conference aimed at achieving a common classification for AP and its complications. Within severe acute pancreatitis, of which necrotizing pancreatitis is a part, organ failure and local complications can be seen (necrosis, pseudocyst, and abscess). Multiple organ failure and pancreatic necrosis are the factors that determine the prognosis. Half of the mortalities are observed within a period of 1 or 2 weeks. Necrotizing pancreatitis makes up for the 10–20% of AP cases. Severe pancreatitis has a high mortality rate and functional diseases like diabetes are seen in one-third to one-fifth of the recovered patients.³While the mortality rates are about 10% in the presence of sterile pancreatic necrosis, they go up over 30% in the existence of infected necrosis.¹ Regarding acute necrotizing pancreatitis, there is still no consensus on surgical indications and the time of surgical intervention, the surgical method to be used, and which patients need conservative treatment and which ones need surgical treatment. The goal in the surgical treatment of acute necrotizing pancreatitis is to isolate the necrotic tissue that might cause sepsis and multiple organ failure and to reduce the risk of mortality. The timing of necrosectomy as well as the way in which necrosectomy is performed is significant in necrotizing pancreatitis. The issue of the possibility that necrosectomy can be performed through minimally-invasive interventions instead of open surgery is still being discussed.³We planned to investigate the activity of collagenase clostridiopeptidase A (EC 3.424.3), which has never been attempted before in the debridement of experimental pancreatic necrosis (but which has been used for enzymatic debridement), and the enzyme preparation containing the accompanying proteases (Sterile Novuxol^®, Abbott, Uetersen, Germany). We aimed to evaluate the response of the disease to treatment through laboratory and histopathologic data, by using the enzyme preparation to treat necrotizing pancreatitis.