Cell penetrating peptides: Highlighting points in cancer therapy.

Cell-penetrating peptides (CPPs), first identified in HIV a few decades ago, deserved great attention in the last two decades; especially to support the penetration of anticancer drug means. In the drug delivery discipline, they have been involved in various approaches from mixing with hydrophobic drugs to the use of genetically conjugated proteins. The early classification as cationic and amphipathic CPPs has been extended to a few more classes such as hydrophobic and cyclic CPPs so far. Developing potential sequences utilized almost all methods of modern science: choosing high-efficiency peptides from natural protein sequences, sequence-based comparison, amino acid substitution, obtaining chemical and/or genetic conjugations, in silico approaches, in vitro analysis, animal experiments, etc. The bottleneck effect in this discipline reveals the complications that modern science faces in drug delivery research. Most CPP-based drug delivery systems (DDSs) efficiently inhibited tumor volume and weight in mice, but only in rare cases reduced their levels and continued further processes. The integration of chemical synthesis into the development of CPPs made a significant contribution and even reached the clinical stage as a diagnostic tool. But constrained efforts still face serious problems in overcoming biobarriers to reach further achievements. In this work, we reviewed the roles of CPPs in anticancer drug delivery, focusing on their amino acid composition and sequences. As the most suitable point, we relied on significant changes in tumor volume in mice resulting from CPPs. We provide a review of individual CPPs and/or their derivatives in a separate subsection.

Toad venom bufadienolides and bufotoxins: An updated review.

Bufadienolides, naturally found in toad venoms having steroid-like structures, reveal antiproliferative effects at low doses. However, their application as anticancer drugs is strongly prevented by their Na+ /K+ -ATPase binding activities. Although several kinds of research were dedicated to moderating their Na+ /K+ -ATPase binding activity, still deeper fundamental knowledge is required to bring these findings into medical practice. In this work, we reviewed data related to anticancer activity of bufadienolides such as bufalin, arenobufagin, bufotalin, gamabufotalin, cinobufotalin, and cinobufagin and their derivatives. Bufotoxins, derivatives of bufadienolides containing polar molecules mainly belonging to argininyl residues, are reviewed as well. The established structures of bufotoxins have been compiled into a one-page figure to review their structures. We also highlighted advances in the structure-modification of the structure of compounds in this class. Drug delivery approaches to target these compounds to tumor cells were discussed in one section. The issues related to extraction, identification, and quantification are separated into another section.

Advances on Delivery of Cytotoxic Enzymes as Anticancer Agents.

Cancer is one of the most serious human diseases, causing millions of deaths worldwide annually, and, therefore, it is one of the most investigated research disciplines. Developing efficient anticancer tools includes studying the effects of different natural enzymes of plant and microbial origin on tumor cells. The development of various smart delivery systems based on enzyme drugs has been conducted for more than two decades. Some of these delivery systems have been developed to the point that they have reached clinical stages, and a few have even found application in selected cancer treatments. Various biological, chemical, and physical approaches have been utilized to enhance their efficiencies by improving their delivery and targeting. In this paper, we review advanced delivery systems for enzyme drugs for use in cancer therapy. Their structure-based functions, mechanisms of action, fused forms with other peptides in terms of targeting and penetration, and other main results from in vivo and clinical studies of these advanced delivery systems are highlighted.

Risk factors and outcome of community onset Pseudomonas aeruginosa bacteraemia in two Malaysian district specialist hospitals.

INTRODUCTION: Despite the ever-growing number of community onset (CO) Pseudomonas aeruginosa (P. aeruginosa) bacteraemia, there is a dearth of district hospital-based research examining this significant infection, which is associated with high mortality. The objectives of this study were as following: (1) to determine the risk factors of CO P. aeruginosa bacteraemia, (2) to compare the 30-day mortality rate between P. aeruginosa and Escherichia coli bacteraemia and (3) to identify the predictors of 30-day mortality for CO gram negative bacteraemia. METHODS: This is a retrospective case control study in Hospital Seri Manjung and Hospital Teluk Intan, Perak, Malaysia. P. aeruginosa bacteraemia cases that occurred between 1st January 2015 to 31st December 2019 were included, whilst E. coli bacteraemia cases that occurred within the same period were recruited successively until 1:2 case control ratio was achieved. Subjects below 12-year-old and those with polymicrobial bacteraemia were excluded. Demographic, clinical and treatment data were collected using pre-tested data collection forms by trained investigators. RESULTS: A total of 61 patients with P. aeruginosa bacteraemia and 122 patients with E. coli bacteraemia were included. Recent admission in the earlier three months, regular haemodialysis, immunosuppressive therapy in the past 30 days, chronic wound/pressure sore at presentation and indwelling urinary catheter at presentation were identified as independent predictors of CO pseudomonal bacteraemia. Whilst older age was identified as a negative predictor of CO Pseudomonal bacteraemia (all p<0.05). The 30-day mortality rate was 34.4% in subjects with P. aeruginosa bacteraemia and 27.0% in those with E. coli bacteraemia (p=0.302). Predictors of 30-day mortality for community onset gram negative bacteraemia were as follow: older age, underlying solid tumours, neutropaenia at presentation, in-patient mechanical ventilation, and inpatient nasogastric tube insertion. Unexpectedly, receipt of inappropriate empirical antibiotics which was switched later (delayed and non-delayed switching) was identified as the negative predictors of mortality (all p<0.05). CONCLUSION: It is prudent to restrict the usage of empirical anti-pseudomonal antibiotics among individuals at risk as liberal usage of broad-spectrum antibiotics engenders emergence of drug resistant organism, particularly in district setting where community onset pseudomonal bacteraemia remains scarce. Subjects with elevated risk of mortality should receive early escalation of care as per sepsis management guidelines.

Statins role in preventing contrast-induced acute kidney injury: a scoping review.

BACKGROUND: Acute renal failure secondary to contrast-induced acute kidney injury (CI-AKI) is one of the most commonly encountered problems in hospitalised patients. The CI-AKI may lead to the development of persistent renal disease, causing significant morbidity and mortality in high-risk patients. Statins are increasingly recognised as effective in preventing CI-AKI. In this review, we reviewed the literature on statin use for prophylaxis of CI-AKI, its potential benefits, and adverse effects. The aim of the present review was to reveal gaps and discrepancies in the available literature, and to identify areas for future research. METHODS: We searched PubMed for articles published up to 2018, using keywords including: "Statins AND contrast-induced kidney injury", "3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors AND contras-induced kidney injury", and "HMG-CoA reductase inhibitors AND contrast induced nephropathy". RESULTS: Various trials and reviews have yielded promising results in terms of statin efficacy. However, conflicting results and a lack of homogeneity in the protocols of these trials have limited the applicability of statin-based therapy in clinical practice. Despite the reported beneficial therapeutic effects of short-term high-dosage statin use in preventing CI-AKI, statin therapy is not yet the standard prophylactic regimen due to widespread heterogeneity in the clinical trials. CONCLUSION: Statin therapy can be used as an adjunct to usual prophylactic measures such as adequate hydration and use of low-volume contrast media. Large well-designed trials on the effects of short-term high-dose statin use in preventing CI-AKI should be conducted, to eliminate any form of discrepancy among results, and to clarify any potential adverse effects.

SAPS 3 is not superior to SAPS 2 in cardiac surgery patients.

OBJECTIVES: Cardiac surgery patients are excluded from SAPS2 but included in SAPS3. Neither score is evaluated for this exclusive population; however, they are used daily. We hypothesized that SAPS3 may be superior to SAPS2 in outcome prediction in cardiac surgery patients. DESIGN: All consecutive patients undergoing cardiac surgery between January 2007 and December 2010 were included in our prospective study. Both models were tested with calibration and discrimination statistics. We compared the AUC of the ROC curves by DeLong's method and calculated OCC values. RESULTS: A total of 5207 patients with mean age of 67.2 ± 10.9 years were admitted to the ICU. The mean length of ICU stay was 4.6 ± 7.0 days and the ICU mortality was 5.9%. The two tested models had acceptable discriminatory power (AUC: SAPS2: 0.777-0.875; SAPS3: 0.757-893). SAPS3 had a low AUC and poor calibration on admission day. SAPS2 had poor calibration on Days 1-6 and 8. CONCLUSIONS: Despite including cardiac surgery patients, SAPS3 was not superior to SAPS2 in our analysis. In this large cohort of ICU cardiac surgery patients, performance of both SAPS models was generally poor. In this subset of patients, neither scoring system is recommended.

Glasgow Coma Scale for outcome prediction after cardiac surgery: is it applicable?

OBJECTIVES: The Glasgow Coma Scale (GCS) is used commonly for assessing patients' neurologic condition and outcome in intensive care units (ICUs); however, its reliability in cardiac surgical patients has been questioned. It has been claimed that active sedation is the cause of its unsuitability for these patients. This study aimed to compare the accuracy of GCS in cardiac surgical patients with and without active sedation to find out if the inapplicability of GCS in surgical patients is related to active sedation. DESIGN: This was an observational cohort study. SETTING: The study was conducted in a cardiac surgical intensive care unit between January 1, 2007 and December 31, 2009. PARTICIPANTS: All consecutive adult cardiac surgical patients were included in this study. INTERVENTIONS: All types of cardiac surgical procedures performed during the study period were included without any exceptions. The study population was divided into 2 groups: sedated and non-sedated. MEASUREMENTS AND MAIN RESULTS: GCS was calculated daily for the first 7 postoperative days. The authors developed a new 4-point neurologic descriptor (ND): (1) neurologically free, (2) ICU psychosis, (3) actively sedated, and (4) documented focal neurologic deficits. The accuracy of both scales (GCS and ND) at predicting ICU mortality was compared by replacing the GCS in the Sequential Organ Failure Assessment (SOFA) score with the new ND, producing a modified SOFA. GCS was not an accurate outcome predictor in non-sedated or sedated patients. The ND was superior to GCS. Correspondingly, the modified SOFA showed a significantly higher accuracy of ICU-mortality prediction than the original SOFA. CONCLUSIONS: Regardless of active sedation, GCS is not accurate at outcome prediction for cardiac surgical patients. The suggested ND is a simple and more accurate risk stratification variable in cardiac surgical ICUs.

Most accurate mutations in SARS-CoV-2 genomes identified in Uzbek patients show novel amino acid changes.

Purpose: The rapid changes in the coronavirus genomes created new strains after the first variation was found in Wuhan in 2019. SARS-CoV-2 genotypes should periodically undergo whole genome sequencing to control it because it has been extremely helpful in combating the virus. Many diagnoses, treatments, and vaccinations have been developed against it based on genome sequencing. With its practical implications, this study aimed to determine changes in the delta variant of SARS-CoV-2 widespread in Uzbekistan during the pandemic by genome sequencing, thereby providing crucial insights for developing effective control strategies that can be directly applied in the field. Design: We meticulously generated 17 high-quality whole-genome sequence data from 48 SARS-CoV-2 genotypes of COVID-19 patients who tested positive by PCR in Tashkent, Uzbekistan. Our rigorous approach, which includes stringent quality control measures and multiple rounds of verification, ensures the accuracy and reliability of our findings. Methods: Our study employed a unique combination of genome sequencing and bioinformatics web tools to analyze amino acid (AA) changes in the virus genomes. This approach allowed us to understand the genetic changes in the delta variant of SARS-CoV-2 widespread in Uzbekistan during the pandemic. Results: Our study revealed significant nucleotide polymorphisms, including non-synonymous (missense) and synonymous mutations in the coding regions of the sequenced sample genomes. These findings, categorized by phylogenetic analysis into the G clade (or GK sub-clade), contribute to our understanding of the delta variant of SARS-CoV-2 widespread in Uzbekistan during the pandemic. A total of 134 mutations were identified, consisting of 65 shared and 69 unique mutations. These nucleotide changes, including one frameshift mutation, one conservative and disruptive insertion-deletion, four upstream region mutations, four downstream region mutations, 39 synonymous mutations, and 84 missense mutations, are crucial in the ongoing battle against the virus. Conclusion: The comprehensive whole-genome sequencing data presented in this study aids in tracing the origins and sources of circulating SARS-CoV-2 variants and analyzing emerging variations within Uzbekistan and globally. The genome sequencing of SARS-CoV-2 from samples collected in Uzbekistan in late 2021, during the peak of the pandemic's second wave nationwide, is detailed here. Following acquiring these sequences, research efforts have focused on developing DNA and plant-based edible vaccines utilizing prevalent SARS-CoV-2 strains in Uzbekistan, which are currently undergoing clinical trials.

Successful management of a massive residual space empyema using intrathoracic vacuum-assisted instillation.

There is no universally accepted single line treatment for residual space empyema. Recently, the vacuum-assisted instillation therapy was applied for wounds in different anatomical positions. However, it has not yet been applied as an intrathoracic management. Herein, we describe the first experience of intrathoracic vacuum-assisted instillation therapy for residual space empyema after extended thoracic surgery. It appears to be an attractive treatment option for patients with large contaminated pleural cavities in preparation for reconstructive surgery.

Mortality prediction after cardiac surgery: blood lactate is indispensible.

BACKGROUND: Blood lactate is accepted as a mortality risk marker in intensive care units (ICUs), especially after cardiac surgery. Unfortunately, most of the commonly used ICU risk stratification scoring systems did not include blood lactate as a variable. We hypothesized that blood lactate alone can predict the risk of mortality after cardiac surgery with an accuracy that is comparable to those of other complex models. We therefore evaluated its accuracy at mortality prediction and compared it with that of other widely used complex scoring models statistically. METHODS: We prospectively collected data of all consecutive adult patients who underwent cardiac surgery between January 1, 2007, and December 31, 2009. By using χ2 statistics, a blood lactate-based scale (LacScale) with only four cutoff points was constructed in a developmental set of patients (January 1, 2007, and May 31, 2008). LacScale included five categories: 0 (≤ 1.7 mmol/L); 1 (1.8-5.9 mmol/L), 2 (6.0-9.3 mmol/L), 3 (9.4-13.3 mmol/L), and 4 (≥ 13.4 mmol/L). Its accuracy at predicting ICU mortality was evaluated in another independent subset of patients (validation set, June 1, 2008, and December 31, 2009) on both study-population level (calibration analysis, overall correct classification) and individual-patient-risk level (discrimination analysis, ROC statistics). The results were then compared with those obtained from other widely used postoperative models in cardiac surgical ICUs (Sequential Organ Failure Assessment [SOFA] score, Simplified Acute Physiology Score II [SAPS II], and Acute Physiology and Chronic Health Evaluation II [APACHE II] score). RESULTS: ICU mortality was 5.8% in 4,054 patients. LacScale had a reliable calibration in the validation set (2,087 patients). It was highly accurate in predicting ICU mortality with an area under the ROC curve (area under curve [AUC]; discrimination) of 0.88. This AUC was significantly larger than that of all the other models (SOFA 0.83, SAPS II: 0.79 and APACHE II: 0.76) according to DeLong's comparison. Integrating the LacScale in those scores further improved their accuracy by increasing their AUCs (0.88, 0.81, and 0.80, respectively). This improvement was also highly significant. CONCLUSION: Blood lactate accurately predicts mortality at both individual patient risk and patient cohort levels. Its precision is higher than that of other commonly used "complex" scoring models. The proposed LacScale is a simple and highly reliable model. It can be used (at bedside without electronic calculation) as such or integrated in other models to increase their accuracy.

Human leukocyte antigen class II alleles (DQB1 and DRB1) as predictors for response to interferon therapy in HCV genotype 4.

Human leukocyte antigens class II play an important role in immune response against HCV. We investigated whether HLA class II alleles influence susceptibility to HCV infection and response to interferon therapy. HLA-DRB1 and -DQB1 loci were genotyped using PCR-SSO Luminex technology. According to our regimen, 41 (66%) of patients achieved sustained virological response to combined treatment of IFN and ribavirin. Frequencies of DQB1*0313 allele and DRB1*04-DRB1*11, DQB1*0204-DQB1*0313, DQB1*0309-DQB1*0313, and DQB1*0313-DQB1*0319 haplotypes were significantly more frequent in nonresponders than in responders. In contrast, DQB1*02, DQB1*06, DRB1*13, and DRB1*15 alleles were significantly more frequent in responders than in nonresponders. Similarly, DRB1*1301, DRB1*1361, and DRB1*1369 alleles and DRB1*1301-DRB1*1328, DRB1*1301-DRB1*1361, DRB1*1301-DRB1*1369, DRB1*1328-DRB1*1361, and DRB1*1328-DRB1*1369 haplotypes were significantly found only in responders. Some alleles and linkages showed significantly different distributions between patient and healthy groups. These alleles may be used as predictors for response to treatment or to susceptibility to HCV infection in the Egyptian population.

Repeat transcranial Doppler ultrasound imaging in Kuwaiti children with sickle cell disease after a 10-year interval: A prospective, cohort study.

Objectives: Transcranial Doppler imaging (TCDI) of the cerebral arteries is the method of choice to predict patients with sickle cell disease (SCD) at risk for stroke. This study reports TCDI follow-up of cerebral blood flow in a cohort of Kuwaiti children with SCD after a 10-year interval. Methods: Twenty-one pediatric patients with SCD, aged 16.0 ± 1.6 years were initially studied when they were aged 6.5 ± 1.2 years. TCDI scanning was carried out using a phased-array transducer of 1-3 MHz through the trans-temporal window. Peak systolic velocity (PSV), end-diastolic velocity (EDV), time-averaged mean of the maximum velocity (TAMMV), resistive index (RI), and pulsatility index (PI) were obtained in the anterior and posterior Circle of Willis vessels. Results: The follow-up indices were mostly lower than in the initial study although they remained within the normal range in all the arteries. TAMMV was less than 170 cm/s, and PSV did not exceed 200 cm/s in all vessels. The initial and follow-up TAMMV (mean ± SD) were: 77.3 ± 20.9 and 71.6 ± 9.9 in the terminal internal carotid artery, 94.3 ± 25.8 and 82 ± 18.2 in the middle cerebral artery, 76.6 ± 25.6 and 70.6 ± 10.7 in the anterior cerebral artery, and 59.1 ± 15.8 and 63.9 ± 8.5 in the posterior cerebral artery, respectively. The mean differences between the old and follow-up data for RI, and PI were statistically significant (p < 0.05). Conclusions: Kuwaiti patients with SCD appear to be largely protected from cerebral artery vasculopathy in childhood.

Outcome of abdominosacral resection for locally advanced primary and recurrent rectal cancer.

BACKGROUND: The aim was to assess the indications for and outcomes of abdominosacral resection for patients with locally advanced primary and recurrent rectal cancer. METHODS: Consecutive patients undergoing abdominosacral resection between January 2006 and December 2011 were identified from a prospectively maintained database. The main endpoints were 3-year local recurrence-free (LRFS) and disease-free (DFS) survival. RESULTS: Thirty patients underwent abdominosacral resection, 22 for recurrent rectal cancer and eight for locally advanced primary cancer. Sacrectomy was performed at S1/2 in five, S3 in 11 and S4/5 in 14 patients. R0 resection was achieved in 23 patients; all seven positive margins (R1) were in patients with recurrent disease. There were no deaths in hospital or within 30 days. S1/2 sacrectomy was associated with the highest rate of major complications (60 per cent versus 27 and 29 per cent for S3 and S4/5 respectively) and long-term complications (60, 36 and 14 per cent). Overall 3-year LRFS was 66 per cent and 3-year DFS was 55 per cent. Both were significantly better in patients with negative compared with positive margins (LRFS: 87 versus 0 per cent, P < 0.001; DFS: 71 versus 0 per cent, P = 0.033). CONCLUSION: Abdominosacral resection was associated with long-term survival in carefully selected patients with advanced rectal cancer. Postoperative complications were common and often multiple. Sacrectomy for locally advanced primary rectal cancer was associated with a low margin-positive rate and should be considered as an acceptable treatment. Margin-positive resection was associated with poor survival outcomes and should be avoided.

Mannosylated engineered trichosanthin-legumain protein vaccine hydrogel for breast cancer immunotherapy.

The development of cancer vaccines based on tumor-associated antigens is hurdled by lack of an efficient adjuvant and insufficient efficacy. To improve the efficacy of vaccines, a genetically-engineered method was employed in this work to achieve the codelivery of antigen and adjuvant to enhance immune responses. Trichosanthin is a plant-derived protein that possesses cancer immune stimulation function. A genetically engineered protein vaccine composed of trichosanthin (adjuvant) and legumain domain (a peptidic antigen) was constructed, which was further chemically modified with mannose for targeting dendritic cells (DCs). The method is facile and ready for scaling up for massive production. Such a "two-in-one" vaccine is advantageous for codelivery for augmenting the immune responses. The vaccine inhibited the tumors by triggering a robust cytotoxic T lymphocyte response in the orthotopic-breast-tumor mice. Furthermore, the vaccine was loaded into the temperature-sensitive hydrogel based on Pluronic F127 for implanting use in the post-surgical site. The sustained-released vaccine from the hydrogel inhibited not only the tumor recurrence but also the lung metastases of breast cancer. These findings demonstrated that it was a safe and effective vaccination for breast cancer immunotherapy in a prophylactical and therapeutical manner for remodeling the tumor immune microenvironment and arresting tumor growth.

Biomimetic camouflage delivery strategies for cancer therapy.

Cancer remains a significant challenge despite the progress in developing different therapeutic approaches. Nanomedicine has been explored as a promising novel cancer therapy. Recently, biomimetic camouflage strategies have been investigated to change the bio-fate of therapeutics and target cancer cells while reducing the unwanted exposure on normal tissues. Endogenous components (e.g., proteins, polysaccharides, and cell membranes) have been used to develop anticancer drug delivery systems. These biomimetic systems can overcome biological barriers and enhance tumor cell-specific uptake. The tumor-targeting mechanisms include ligand-receptor interactions and stimuli-responsive (e.g., pH-sensitive and light-sensitive) delivery. Drug delivery carriers composed of endogenous components represent a promising approach for improving cancer treatment efficacy. In this paper, different biomimetic drug delivery strategies for cancer treatment are reviewed with a focus on the discussion of their advantages and potential applications.

Body composition, growth performance and enzyme activities of Labeo rohita fed different commercial fish feeds.

We have evaluated the effects of different fish feeds on the body composition, growth, and enzyme activities of Labeo rohita (Rohu). In total, 240 fishes between the average weights of 24.77±2.15g were studied. The treatments were applied in a completely randomized design, with 4 treatments of 60 fishes each. Treatments consisted of four different fish feeds [Oryza (T1), AMG (T2), Aqua (T3), and Supreme (T4)]. Body composition, growth performance, and enzyme activities were evaluated. There was a significant variation in performance of fishes fed with different type of feed; as fishes having Oryza feed showed the highest weight gain, specific growth rate (SGR), and best feed conversion ratio (FCR) as compared to other groups that were considered to be significant (P ≤ 0.05). High net weight gain was obtained in T4 when compared with T2 and T3. FCR value of T4 was less than T1 but higher than T2, T3 and T2, which showed the lowest values. The specific growth rate was recorded as average in T4, but T2 led a high SGR than T3. Similarly, crude protein level and digestive enzymes activity was recorded significantly highest in fed with Oryza (T1) as compared to AMG (T2), Aqua (T3), and Supreme (T4). Water quality parameters were recorded significant in all treatments except pH and DO of treatment (T1), significantly different from other treatments. It was concluded that Rohu (Labeo rohita) could show a promising growth rate and protease enzyme activity when fed with the Oryza feed of 25% protein.

Objective method to evaluate the competency of residents in cardiac surgery.

OBJECTIVES: Cardiac surgery training has become more challenging as patients and their diagnoses become more complex. Our goal was to develop a multicategorical assessment model for evaluating residents in cardiac surgery. This model is intended to ensure goal-directed progress in their training as well as to recognize and support their surgical talents. METHODS: We developed a new questionnaire in a multistage, 3-round process based on the Delphi method 'estimate-talk-estimate', using 55 competencies, including 38 general and 17 domain-specific competencies. Each competency is evaluated with 1 or more questions, to which 1 (not competent) to 6 (very competent) points can be chosen as an answer. RESULTS: The resulting model achieved 2 main goals: first, presenting a well-defined competency list for cardiac surgical training and second, providing an objective and realistic evaluation of trainees' abilities. Residents were assessed by all trainers to achieve a high level of objectivity. CONCLUSIONS: This evaluation model is highly objective, because residents are evaluated by multiple trainers. It allows individual support and enables better transparency in residency training. Talents and skills are evaluated, recognized and adopted as a base for individual feedback and personalized training programmes.

Magnetism-mediated targeting hyperthermia-immunotherapy in "cold" tumor with CSF1R inhibitor.

Background: Immunotherapy has profoundly changed the landscape of cancer management and represented the most significant breakthrough. Yet, it is a formidable challenge that the majority of cancers - the so-called "cold" tumors - poorly respond to immunotherapy. To find a general immunoregulatory modality that can be applied to a broad spectrum of cancers is an urgent need. Methods: Magnetic hyperthermia (MHT) possesses promise in cancer therapy. We develop a safe and effective therapeutic strategy by using magnetism-mediated targeting MHT-immunotherapy in "cold" colon cancer. A magnetic liposomal system modified with cell-penetrating TAT peptide was developed for targeted delivery of a CSF1R inhibitor (BLZ945), which can block the CSF1-CSF1R pathway and reduce M2 macrophages. The targeted delivery strategy is characterized by its magnetic navigation and TAT-promoting intratumoral penetration. Results: The liposomes (termed TAT-BLZmlips) can induce ICD and cause excessive CRT exposure on the cell surface, which transmits an "eat-me" signal to DCs to elicit immunity. The combination of MHT and BLZ945 can repolarize M2 macrophages in the tumor microenvironment to relieve immunosuppression, normalize the tumor blood vessels, and promote T-lymphocyte infiltration. The antitumor effector CD8+ T cells were increased after treatment. Conclusion: This work demonstrated that TAT-BLZmlips with magnetic navigation and MHT can remodel tumor microenvironment and activate immune responses and memory, thus inhibiting tumor growth and recurrence.

Mutational spectrum of NF1 gene in 24 unrelated Egyptian families with neurofibromatosis type 1.

BACKGROUND: Neurofibromatosis 1 (NF1; OMIM# 162200) is a common autosomal dominant genetic disease [incidence: ~1:3500]. In 95% of cases, clinical diagnosis of the disease is based on the presence of at least two of the seven National Institute of Health diagnostic criteria. The molecular pathology underlying this disorder entails mutation in the NF1 gene. The aim of this study was to investigate clinical and molecular characteristics of a cohort of Egyptian NF1 patients. METHOD: This study included 35 clinically diagnosed NF1 patients descending from 25 unrelated families. Patients had ≥2 NIH diagnostic criteria. Examination of NF1 gene was done through direct cDNA sequencing of multiple overlapping fragments. This was supplemented by NF1 multiple ligation dependent probe amplification (MLPA) analysis of leucocytic DNA. RESULTS: The clinical presentations encompassed, café-au-lait spots in 100% of probands, freckling (52%), neurofibromas (20%), Lisch nodules of the iris (12%), optic pathway glioma (8%), typical skeletal disorders (20%), and positive family history (32%). Mutations could be detected in 24 families (96%). Eight mutations (33%) were novel. CONCLUSION: This study illustrates the underlying molecular pathology among Egyptian NF1 patients for the first time. It also reports on 8 novel mutation expanding pathogenic mutational spectra in the NF1 gene.

Third-generation mobile phones (UMTS) do not interfere with permanent implanted pacemakers.

AIMS: Third-generation mobile phones, UMTS (Universal Mobile Telecommunication System), were recently introduced in Europe. The safety of these devices with regard to their interference with implanted pacemakers is as yet unknown and is the point of interest in this study. METHODS AND RESULTS: The study comprised 100 patients with permanent pacemaker implantation between November 2004 and June 2005. Two UMTS cellular phones (T-Mobile, Vodafone) were tested in the standby, dialing, and operating mode with 23 single-chamber and 77 dual-chamber pacemakers. Continuous surface electrocardiograms (ECGs), intracardiac electrograms, and marker channels were recorded when calls were made by a stationary phone to cellular phone. All pacemakers were tested under a "worst-case scenario," which includes a programming of the pacemaker to unipolar sensing and pacing modes and inducing of a maximum sensitivity setting during continuous pacing of the patient. Patients had pacemaker implantation between June 1990 and April 2005. The mean age was 68.4 +/- 15.1 years. Regardless of atrial and ventricular sensitivity settings, both UMTS mobile phones (Nokia 6650 and Motorola A835) did not show any interference with all tested pacemakers. In addition, both cellular phones did not interfere with the marker channels and the intracardiac ECGs of the pacemakers. CONCLUSION: Third-generation mobile phones are safe for patients with permanent pacemakers. This is due to the high-frequency band for this system (1,800-2,200 MHz) and the low power output between 0.01 W and 0.25 W.