Contemporary treatment approaches for metastatic colorectal cancer driven by BRAF V600 mutations

The treatment of metastatic colorectal cancer (mCRC) harboring BRAF V600 mutations is challenging. These tumors are often refractory to standard treatment. Therefore, the patients may exhibit rapid clinical deterioration, depriving them of the chance to receive salvage therapy. In newly diagnosed patients with good performance status, the administration of an intensive chemotherapy regimen like FOLFOXIRI (5-fluorouracil, leucovorin, oxaliplatin, and irinotecan) along with the antiangiogenic agent bevacizumab can modify this aggressive behavior of the disease and improve patient clinical outcomes. The recently published results of the BEACON (Binimetinib, Encorafenib, and Cetuximab Combined to Treat BRAF-Mutant Colorectal Cancer) study demonstrated that a combination therapy consisting of BRAF, epidermal growth factor receptor, and mitogen-activated protein kinase kinase inhibitors could be a useful second-or third-line alternative. This review summarizes the current treatment strategies for BRAF-mutant mCRC.     

Polygenic analysis suggests the involvement of calcium signaling in executive function in schizophrenia patients

European Archives of Psychiatry and Clinical Neuroscience - Cognitive deficits are increasingly recognized as a core dimension rather than a consequence of schizophrenia (SCZ). The previous...     

Bahcesehir long-term population-based screening compared to National Breast Cancer Registry Data: effectiveness of screening in an emerging country

PURPOSEWe aimed to show the effects of long-term screening on clinical, pathologic, and survival outcomes in patients with screen-detected breast cancer and compare these findings with breast cancer patients registered in the National Breast Cancer Registry Data (NBCRD).METHODSWomen aged 40–69 years, living in Bahcesehir county, Istanbul, Turkey, were screened every 2 years using bilateral mammography. The Bahcesehir National Breast Cancer Registry Data (BMSP) data were collected during a 10-year screening period (five rounds of screening). BMSP data were compared with the NBCRD regarding age, cancer stage, types of surgery, tumor size, lymph node status, molecular subtypes, and survival rates.RESULTSDuring the 10-year screening period, 8758 women were screened with 22621 mammograms. Breast cancer was detected in 130 patients; 51 (39.2%) were aged 40–49 years. The comparison of breast cancer patients in the two programs revealed that BMSP patients had earlier stages, higher breast-conserving surgery rates, smaller tumor size, more frequent negative axillary nodal status, lower histologic grade, and higher ductal carcinoma in situ rates than NBCRD patients (p = 0.001, for all).CONCLUSIONThese results indicate the feasibility of successful population-based screening in middle-income countries.

Breast cancer is the most frequent cancer and cause of cancer-related deaths among Turkish women, as well as globally (1–5). Although the incidence of breast cancer increases every year, mortality rates are decreasing in developed countries because of nationwide screening programs and modern treatment options (5, 6). An invited mammography screening program for women aged between 40 and 69 years revealed a 60% reduction in cancer-related 10-year mortality in a landmark study (7). A systematic review of Myers et al. (8) showed that breast cancer screening reduced mortality by 20% in average-risk women of all age groups. However, this review did not evaluate the differences between annual and biannual mammographic screening.In 2004, the Cancer Control Department of Turkey recommended biannual mammographic screening for women aged 50–69 years, based on European Guidelines. The population of Turkey is relatively young, and almost half of all breast cancer patients in Turkey are younger than 50 years. According to and National Breast Cancer Registry Data (NBCRD) reports, the starting age for mammography screening was set as 40 years. The Bahcesehir Mammographic Screening Program (BMSP) was the first organized population-based 10-year (2009–2019) mammography screening program in Turkey, a middle-income country.Turkish Federation of Breast Diseases Societies started a voluntary data registry program that was provided by breast surgeons working in secondary or tertiary hospitals. This program aimed to collect detailed information of breast cancer patients and to pool comprehensive country-specific breast cancer data. This registry, namely the NBCRD, was the first specified database on breast cancer in the country and was started in 2005, before the BMSP (9). Data from 36 centers were collected for 10 years. However, the cancer registry is a standard database containing general information as defined by the International Agency for Research on Cancer standards.The aim of this study was to show the feasibility of a population-based breast cancer screening program in an emerging, middle-income country, Turkey. The objective of our study was to evaluate the effectiveness of a population-based breast cancer screening program by comparing it with NBCRD data.     

Effect of polymer type on characteristics of buccal tablets using factorial design

A two factor three level factorial design was used to investigate the effects of carbopol and cationic hydrophilic polymers which have a common use in buccal drug formulations. Statistical models with interaction terms were derived to evaluate influence of carbopol (X1) and chitosan (X2) on tablet disintegration (Y1) and dissolution (Y2), mechanical properties (Y3), swelling (Y4). Tablet disintegration studies were carried out using two different pH environments within buccal region pH limits and also two different commonly used dissolution methods for buccal tablets were also investigated to compare the effect of polymer type on dissolution. Polymer type and ratio affect the characteristics of the buccal tablets due to their different physicochemical behavior at buccal pH. Also significant variances between dissolution profiles for buccal tablets, using either USP Paddle or flow through cell methods were found. These results indicate that both polymer type and ratio as well as combination of them effects the drug behavior in different ways.     

Comparison of different cryopreservation protocols for human umbilical cord tissue as source of mesenchymal stem cells

The main purpose of this study is to establish an effective cryopreservation protocol for the umbilical cord tissue as a source of mesenchymal stem cells (MSCs). In this context, it was aimed to use a cryoprotectant that could be an alternative to dimethyl sulfoxide (DMSO) which is commonly used despite the toxic side effects. Therefore, two different cryopreservation solutions were prepared using 10% DMSO and 10% 1,2 propanediol (PrOH). The fresh tissue group that was not performed cryopreservation was used as the control group. Following the cryopreservation step, MSCs were isolated from all groups and compared with each other to assess the efficiency of the cryopreservation solutions. The comparison was performed in terms of followings: morphology, immunophenotypes, growth kinetics, differentiation, and ultrastructural features. Based on the results, there were no significant morphological and immunophenotypic differences between the MSCs isolated from cryopreserved tissue groups and the MSCs isolated from the fresh tissue group. According to the growth kinetic analysis, the cells isolated from the PrOH group had a lower proliferation rate than the cells isolated from the fresh tissue. However, there was no significant difference between the cryopreserved groups in this respect. Osteogenic and adipogenic differentiation was observed in all groups. Upon comparison of the cryopreserved groups, PrOH group was discovered to hold a minor superiority in terms of these modes of differentiation. These results suggest that PrOH, which is considered as a cryoprotectant with low toxicity, could be used as a preferred cryoprotectant instead of DMSO concerning the process of cryopreservation of the umbilical cord.     

β‐adrenergic Receptor Blocker ICI 118,551 Selectively Increases Intermediate‐Conductance Calcium‐Activated Potassium Channel (IKCa)‐Mediated Relaxations in Rat Main Mesenteric Artery

Endothelial IK_Ca and/or SK_Ca channels play an important role in the control of vascular tone by participating in endothelium‐dependent relaxation. Whether β‐AR antagonists, mainly used in hypertension, affect endothelial K_Ca channel function is unknown. In this study, we examined the effect of the β2‐AR antagonist and inverse agonist ICI 118,551 on the IK_Ca/SK_Ca channel activity by assessing functional relaxation responses to several agonists that stimulate these channels. Mesenteric arterial rings isolated from male Sprague Dawley mounted to organ baths. Acetylcholine elicited IK_Ca‐ and SK_Ca‐mediated relaxations that were abolished by TRAM‐34 and apamin, respectively. ICI 118,551, which did not dilate the arteries per se, increased the IK_Ca‐mediated relaxations, whereas SK_Ca‐mediated relaxations remained unaltered. Same potentiating effect was also detected on the IK_Ca‐mediated relaxations to carbachol and A23187, but not to NS309. Neither acetylcholine‐induced nitric oxide‐mediated relaxations nor SNP relaxations changed with ICI 118,551. The PKA inhibitor KT‐5720, the selective β2‐AR agonist salbutamol, the selective β2‐AR antagonist butoxamine, the non‐selective β‐AR antagonist propranolol, and the inverse agonists carvedilol or nadolol failed to affect the IK_Ca‐mediated relaxations. ICI 118,551‐induced increase was not reversed by salbutamol or propranolol as well. Besides, low potassium‐induced relaxations in endothelium‐removed arteries remained the same in the presence of ICI 118,551. These data demonstrate a previously unrecognized action of ICI 118,551, the ability to potentiate endothelial IK_Ca channel‐mediated vasodilation, through a mechanism independent of β2‐AR antagonistic or inverse agonistic action. Instead, the enhancement of acetylcholine relaxation seems likely to occur by a mechanism secondary to endothelial calcium increase.