Fractionated photoimmunotherapy stimulates an anti-tumour immune response: an integrated mathematical and in vitro study.

BACKGROUND: Advanced epithelial ovarian cancer (EOC) has high recurrence rates due to disseminated initial disease presentation. Cytotoxic phototherapies, such as photodynamic therapy (PDT) and photoimmunotherapy (PIT, cell-targeted PDT), have the potential to treat disseminated malignancies due to safe intraperitoneal delivery. METHODS: We use in vitro measurements of EOC tumour cell and T cell responses to chemotherapy, PDT, and epidermal growth factor receptor targeted PIT as inputs to a mathematical model of non-linear tumour and immune effector cell interaction. The model outputs were used to calculate how photoimmunotherapy could be utilised for tumour control. RESULTS: In vitro measurements of PIT dose responses revealed that although low light doses (<10 J/cm2) lead to limited tumour cell killing they also increased proliferation of anti-tumour immune effector cells. Model simulations demonstrated that breaking up a larger light dose into multiple lower dose fractions (vis-à-vis fractionated radiotherapy) could be utilised to effect tumour control via stimulation of an anti-tumour immune response. CONCLUSIONS: There is promise for applying fractionated PIT in the setting of EOC. However, recommending specific fractionated PIT dosimetry and timing will require appropriate model calibration on tumour-immune interaction data in human patients and subsequent validation of model predictions in prospective clinical trials.

Simulating tumor volume dynamics in response to radiotherapy: Implications of model selection.

From the beginning of the usage of radiotherapy (RT) for cancer treatment, mathematical modeling has been integral to understanding radiobiology and for designing treatment approaches and schedules. There has been extensive modeling of response to RT with the inclusion of various degrees of biological complexity. In this study, we compare three models of tumor volume dynamics: (1) exponential growth with RT directly reducing tumor volume, (2) logistic growth with direct tumor volume reduction, and (3) logistic growth with RT reducing the tumor carrying capacity with the objective of understanding the implications of model selection and informing the process of model calibration and parameterization. For all three models, we: examined the rates of change in tumor volume during and RT treatment course; performed parameter sensitivity and identifiability analyses; and investigated the impact of the parameter sensitivity on the tumor volume trajectories. In examining the tumor volume dynamics trends, we coined a new metric - the point of maximum reduction of tumor volume (MRV) - to quantify the magnitude and timing of the expected largest impact of RT during a treatment course. We found distinct timing differences in MRV, dependent on model selection. The parameter identifiability and sensitivity analyses revealed the interdependence of the different model parameters and that it is only possible to independently identify tumor growth and radiation response parameters if the underlying tumor growth rate is sufficiently large. Ultimately, the results of these analyses help us to better understand the implications of model selection while simultaneously generating falsifiable hypotheses about MRV timing that can be tested on longitudinal measurements of tumor volume from pre-clinical or clinical data with high acquisition frequency. Although, our study only compares three particular models, the results demonstrate that caution is necessary in selecting models of response to RT, given the artifacts imposed by each model.

Identifying patients at risk for hereditary myeloid malignancy syndromes incorporating a novel, self-administered questionnaire to an initial screening platform.

INTRODUCTION: Four to 10% of cases of myeloid malignancies are inherited. We report our experience on hereditary myeloid malignancy syndromes (HMMS) incorporating a novel questionnaire in the screening platform for patients with myeloid malignancies and aplastic anemia. METHODS: The questionnaire was sent via electronic patient portal prior to clinic visits. Patients screened positive based on responses to questionnaire items, presence of suspicion disease characteristics (young age, family history, monosomy 7 etc.) and/or presence of signs of HMMS. Those deemed at-risk based on questionnaire responses, clinical features and/or somatic mutation profile were offered germline testing. RESULTS: A total of 408 patients were screened, 141 (35%) were deemed at-risk. Fifty-four (38%) of at-risk patients were seen in the genetics clinic. Forty-one (76%) of the patients seen agreed to germline testing and 13 declined due to cost or personal decision. Twenty pathogenic (P)/likely-pathogenic (LP) germline mutations were identified in 16 (39%) of the tested patients. Five patients also had a variant of uncertain significance (VUS) and an additional 13 had at least 1 VUS without P/LP mutations (total 29 VUS's were found in 18 (44%) of tested patients). The median age of diagnosis for patients with P/LP mutations was 56 years versus 66 years in the entire cohort. CONCLUSION: Incorporating an electronic questionnaire is an effective screening method for HMMS. Many patients declined testing due to cost. These results highlight the importance of germline testing in patients with myeloid malignancies, further research in HMMS, and coverage by healthcare plans.

Physician-scientist or basic scientist? Exploring the nature of clinicians' research engagement.

Theoretical understanding of what motivates clinician researchers has met with some success in launching research careers, but it does not account for professional identification as a factor determining sustained research engagement over the long-term. Deeper understanding of clinicians' research-related motivation may better foster their sustained research engagement post-training and, by extension, the advancement of medicine and health outcomes. This study used an integrated theoretical framework (Social Cognitive Career Theory and Professional Identity Formation) and appreciative inquiry to explore the interplay of professional identification and research context in shaping post-training research success narratives. To foreground professional identification, 19 research-active clinicians and 17 basic scientists served as interviewees. A multi-institutional, multi-national design was used to explore how contextual factors shape external valuation of research success. The findings suggest that research-active clinicians do not identify as the career scientists implied by the modern physician-scientist construct and the goal of many clinician research-training programs. Their primary identification as care providers shapes their definition of research success around extending their clinical impact; institutional expectations and prevailing healthcare concerns that value this aim facilitate their sustained research engagement. Integrated developmental and organizational interventions adaptive to research context and conducive to a wider range of medical inquiry may better leverage clinicians' direct involvement in patient care and advance progress toward human health and well-being.

Short-Wave Infrared Quantum Dots with Compact Sizes as Molecular Probes for Fluorescence Microscopy.

Materials with short-wave infrared (SWIR) emission are promising contrast agents for in vivo animal imaging, providing high-contrast and high-resolution images of blood vessels in deep tissues. However, SWIR emitters have not been developed as molecular labels for microscopy applications in the life sciences, which require optimized probes that are bright, stable, and small. Here, we design and synthesize semiconductor quantum dots (QDs) with SWIR emission based on HgxCd1-xSe alloy cores red shifted to the SWIR by epitaxial deposition of thin HgxCd1-xS shells with a small band gap. By tuning alloy composition alone, the emission can be shifted across the visible-to-SWIR (VIR) spectra while maintaining a small and equal size, allowing direct comparisons of molecular labeling performance across a broad range of wavelength. After coating with click-functional multidentate polymers, the VIR-QD spectral series has high quantum yield in the SWIR (14-33%), compact size (13 nm hydrodynamic diameter), and long-term stability in aqueous media during continuous excitation. We show that these properties enable diverse applications of SWIR molecular probes for fluorescence microscopy using conjugates of antibodies, growth factors, and nucleic acids. A broadly useful outcome is a 10-55-fold enhancement of the signal-to-background ratio at both the single-molecule level and the ensemble level in the SWIR relative to visible wavelengths, primarily due to drastically reduced autofluorescence. We anticipate that VIR-QDs with SWIR emission will enable ultrasensitive molecular imaging of low-copy number analytes in biospecimens with high autofluorescence.

Hepatoprotective and antioxidant activities of Annona squamosa seed extract against alcohol-induced liver injury in Sprague Dawley rats.

Alcohol is regarded as the third most common cause of death after hypertension and smoking. Its long-term excess exposure leads to alcoholic liver disease (ALD) and liver injury, a worldwide health problem without efficient therapy. As there is no reliable liver protective drugs in allopathic medical practices, herbs play a major role in the management of liver diseases. Thus, the present study was designed to evaluate hepatoprotective activity of Annona squamosa seed extract against alcohol-induced liver injury in Sprague Dawley rats. Liver toxicity was induced by 50% alcohol at dose level of 12 ml/kg po each, for 8 days. Ethanolic extract of A. squamosa seed (EEAS) at dose of 200 and 400 mg/kg po were administered once daily for 8 consecutive days. The hepatoprotective activity of EEAS was assessed in experimental rats using various biochemical parameters like ALT, AST, ALP, LDH, SBL, albumin, total cholesterol, and total protein; and antioxidant parameters like SOD, CAT, GSH, and TBARS. It demonstrated that the treatment with EEAS significantly (p < 0.05-p < 0.001) and dose-dependently prevented the alcohol-induced increase in serum levels of hepatic enzymes and significantly increased the levels of SOD, CAT, and GSH. It also significantly decreased the level of MDA. Histopathology of the liver tissues showed that EEAS attenuated the hepatocellular necrosis and led to regeneration and repair of cells toward normal. Results of this study strongly indicated the protective effect of A. squamosa against alcohol-induced liver injury which may be attributed to its hepatoprotective and antioxidant activities.

Herpes Zoster During Immunosuppressive Therapy For Autoimmune Diseases.

BACKGROUND: Patients on immunosuppressive therapy are at a greater risk for herpes zoster reactivation and are more likely to have adverse outcomes. Propylactic antivrials and vaccinations may potentially prevent these complications. METHODS: Medical literature addressing the clinical course and therapy of herpes zoster in patients receiving immunosuppressive therapy for autoimmune disorders, and the roles of anti-viral prophylaxis and vaccination was reviewed. Research databases including PubMed, Ovid, Medline, Google Scholar and Cochrane were utilized. RESULTS: Acyclovir and its derivatives are most commonly used in this setting for treatment and reduction of post-zoster complications. Foscarnet may be used for acyclovir-resistant strains. At both conventional and ultralow doses, acyclovir has proven effective when used as prophylaxis, reducing the incidence of zoster and its complications in immunosuppressed patients. Additionally, ultra-low doses are associated with significantly reduced side effects. The zoster vaccine, Zostavax, a live-attenuated vaccine has shown promising results in several clinical trials. However, live-attenuated vaccines should be cautiously used in immunosuppressed patients. For patients who require immunosuppressive therapy, vaccination 2-3 months prior to therapy may be appropriate. CONCLUSIONS: Prophylactic antiviral therapy and vaccination help significantly reduce morbidity and mortality from zoster reactivation in patients receiving immunosuppressive therapy.

Lipoprotein Nanoplatelets: Brightly Fluorescent, Zwitterionic Probes with Rapid Cellular Entry.

Semiconductor nanoplatelets (NPLs) are planar nanocrystals that have recently attracted considerable attention due to their quantum-well-like physics, atomically precise thickness, and unique photophysical properties such as narrow-band fluorescence emission. These attributes are of potential interest for applications in biomolecular and cellular imaging, but it has been challenging to colloidally stabilize these nanocrystals in biological media due to their large dimensions and tendency to aggregate. Here we introduce a new colloidal material that is a hybrid between a NPL and an organic nanodisc composed of phospholipids and lipoproteins. The phospholipids adsorb to flat surfaces on the NPL, and lipoproteins bind to sharp edges to enable monodisperse NPL encapsulation with long-term stability in biological buffers and high-salt solutions. The lipoprotein NPLs (L-NPLs) are highly fluorescent, with brightness comparable to that of wavelength-matched quantum dots at both the ensemble and single-molecule levels. They also exhibit a unique feature of rapid internalization into living cells, after which they retain their fluorescence. These unique properties suggest that L-NPLs are particularly well suited for applications in live-cell single-molecule imaging and multiplexed cellular labeling.

Multidentate Polymer Coatings for Compact and Homogeneous Quantum Dots with Efficient Bioconjugation.

Quantum dots are fluorescent nanoparticles used to detect and image proteins and nucleic acids. Compared with organic dyes and fluorescent proteins, these nanocrystals have enhanced brightness, photostability, and wavelength tunability, but their larger size limits their use. Recently, multidentate polymer coatings have yielded stable quantum dots with small hydrodynamic dimensions (≤10 nm) due to high-affinity, compact wrapping around the nanocrystal. However, this coating technology has not been widely adopted because the resulting particles are frequently heterogeneous and clustered, and conjugation to biological molecules is difficult to control. In this article we develop new polymeric ligands and optimize coating and bioconjugation methodologies for core/shell CdSe/Cd(x)Zn(1-x)S quantum dots to generate homogeneous and compact products. We demonstrate that "ligand stripping" to rapidly displace nonpolar ligands with hydroxide ions allows homogeneous assembly with multidentate polymers at high temperature. The resulting aqueous nanocrystals are 7-12 nm in hydrodynamic diameter, have quantum yields similar to those in organic solvents, and strongly resist nonspecific interactions due to short oligoethylene glycol surfaces. Compared with a host of other methods, this technique is superior for eliminating small aggregates identified through chromatographic and single-molecule analysis. We also demonstrate high-efficiency bioconjugation through azide-alkyne click chemistry and self-assembly with hexa-histidine-tagged proteins that eliminate the need for product purification. The conjugates retain specificity of the attached biomolecules and are exceptional probes for immunofluorescence and single-molecule dynamic imaging. These results are expected to enable broad utilization of compact, biofunctional quantum dots for studying crowded macromolecular environments such as the neuronal synapse and cellular cytoplasm.

Venous thromboembolism following hematopoietic stem cell transplantation-a systematic review and meta-analysis.

Venous thromboembolism (VTE) is a common complication of hematopoietic stem cell transplantation (HSCT). Graft-versus-host disease (GVHD) is another complication of HSCT that may modify the risk of VTE. Our objective was to explore the incidence of VTE (deep venous thrombosis and pulmonary embolism) following HSCT and to evaluate its association with GVHD. A comprehensive search of Medline In-Process & Other Non-Indexed Citations, MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Scopus was conducted to search for both retrospective and prospective HSCT studies which had reported VTE. Random-effects meta-analysis was used to pool incidence rates. We included 17 studies reporting on allogeneic- and 10 on autologous-HSCT; enrolling 6693 patients; of which 5 were randomized. The overall incidence of VTE after HSCT was 5 % (4-7 %). Incidence in allogeneic-HSCT was 4 % (2-6 %) and in autologous-HSCT was 4 % (1-15 %). Eleven and nine studies reported data on acute and chronic GVHD, respectively. The incidence of VTE in chronic GVHD was 35 % (20-54 %), whereas in acute GVHD it was 47 % (32-62 %). Based on the results of this meta-analysis, VTE is a fairly common complication after HSCT, emphasizing the importance of assimilating guidelines for both treatment and prophylaxis in this patient population.

Central nervous system prophylaxis in diffuse large B-cell lymphoma.

Central nervous system (CNS) involvement with diffuse large B-cell lymphoma (DLBCL) is a relatively uncommon manifestation; with most cases of CNS involvement occuring during relapse after primary therapy. CNS dissemination typically occurs early in the disease course and is most likely present subclinically at the time of diagnosis in many patients who later relapse in the CNS. CNS relapse in these patients is associated with poor outcomes. Based on a CNS relapse rate of 5% in DLBCL and weighing the benefits against the toxicities, universal application of CNS prophylaxis is not justified. The introduction of rituximab has significantly reduced the incidence of CNS relapse in DLBCL. Different studies have employed other agents for CNS prophylaxis, such as intrathecal chemotherapy and high-dose systemic agents with sufficient CNS penetration. If CNS prophylaxis is to be given, it should be preferably administered during primary chemotherapy. However, there is no strong evidence that supports any single approach for CNS prophylaxis. In this review, we outline different strategies of administering CNS prophylaxis in DLBCL patients reported in literature and discuss their advantages and drawbacks.

Insight into the molecular pathophysiology of myelodysplastic syndromes: targets for novel therapy.

Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by abnormal cellular differentiation and maturation with variable progression to acute leukemia. Over the last decade, scientific discoveries have unraveled specific pathways involved in the complex pathophysiology of MDS. Prominent examples include aberrations in cytokines and their signaling pathways (such as tumor necrosis factor-alpha, interferon-gamma, SMAD proteins), mutations in genes encoding the RNA splicing machinery (SF3B1, SRSF2, ZRSR2, and U2AF1 genes), mutations in genes disrupting the epigenetic machinery (TET2, DNMT3A, DNMT3B, EZH2, ASXL1). In addition, abnormalities in regulatory T-cell dynamics and atypical interactions between the bone marrow microenvironment, stroma and progenitor cells, and abnormal maintenance of telomeres are also notable contributors to the complex pathogenesis of MDS. These pathways represent potential targets for novel therapies. Specific therapies include drugs targeting aberrant DNA methylation and chromatin remodeling, modulating/activating the immune system to enhance tumor-specific cellular immune responses and reduce anomalous cytokine signaling, and blocking abnormal interaction between hematopoietic progenitors and stromal cells.

Comparison of the clinical presentations of Naegleria fowleri primary amoebic meningoencephalitis with pneumococcal meningitis: a case-control study.

BACKGROUND: Primary amoebic meningoencephalitis (PAM) is a rare but fatal infection caused by Naegleria fowleri. The infection is acquired by deep nasal irrigation with infected water. Patients present with signs and symptoms similar to pneumococcal meningitis, leading to delayed diagnosis and treatment and hence high mortality. METHODS: We conducted a case-control study comparing culture proven cases of PAM with pneumococcal meningitis presenting to our center between April 2008 and September 2014. Only patients with blood and/or cerebrospinal fluid cultures positive for Streptococcus pneumoniae during the same time period were included for comparison. RESULTS: There were 19 cases of PAM and pneumococcal meningitis, each. When comparing PAM with pneumococcal meningitis, patients with PAM were more likely to be male (89.5 vs. 36.8 %), younger (mean age: 30 vs. 59 years), present with seizures (42.1 vs. 5.3 %). Both groups of patients presented with similar vital signs and there were no remarkable differences on physical examinations, Glasgow Coma Scale scores, laboratory and radiological investigations and cerebrospinal fluid parameters. PAM was also more likely to present if the city's average maximum temperature was higher in the previous week (mean: 34.6 vs. 30 °C). There was history of fresh water contact in only one patient. On multivariate analysis, PAM was more likely if patients presented when the city's average maximum temperature was high, being young males. CONCLUSION: PAM and pneumococcal meningitis remain virtually indistinguishable; however, these predictive features should be validated in a prospective study and may lead to a viable algorithm for early management of these patients.

Health-Related Anxiety and Hypochondriacal Concerns in Medical Students: A Cross-Sectional Study From Pakistan.

UNLABELLED: Phenomenon: Transient health-related anxiety/hypochondriacal concerns in medical students are well documented. The literature suggests that after studying a particular disease, medical students are likely to consider any symptoms earlier regarded as normal to be signs of the disease they are studying. The aim of this study was to investigate the prevalence of these phenomena and their cognitive and distress aspects among medicals students in Karachi, Pakistan. APPROACH: This was an analytical, cross-sectional study. Self-administered questionnaires comprising demographic details, the Short Health Anxiety Inventory, Medical Students' Disease (MSD) Perception Scale, and MSD Distress Scale were distributed to 1st- through 5th-year medical students. FINDINGS: In total, 513 medical students (66% female) participated. Their mean age was 21 ± 1.6 years. Three hundred seventy-five students (73%) reported having visited a doctor at least once in the past 6 months. Fifty students (9.9%) admitted to having addictions. The overall prevalence of significant hypochondriacal concerns was 11.9% (61 students). The presence of addiction was associated with a greater likelihood of developing significant health-related anxiety (odds ratio = 3.82, p = .003), 95% confidence interval [1.51, 7.11]. Age, gender, medical school, year of medical school, and visits to the doctor in the previous 6 months were not associated with greater likelihood of developing significant health-related anxiety. Second-year medical students experienced a significantly greater degree of worry (MSD-Distress scale) than 5th-year students (M score = 12.6 ± 4.6 vs. 10.7 ± 4.4, p = .04). Insights: The prevalence of substantial hypochondriacal concerns in medical students in Pakistan was low in comparison to similar studies published in literature. Student health physicians should be aware of the true prevalence of hypochondriacal concerns and behavior and not dismiss legitimate complaints. Educational sessions to counteract this phenomenon can be incorporated into the curriculum of undergraduate medicine. By defining heightened awareness of symptoms as a normal process, different coping techniques can be discussed to help medical students reduce their level of stress.

MUMPS MYOCARDITIS: A FORGOTTEN DISEASE?

Mumps is an acute viral illness that follows a self-limiting course but up to 10% of cases have a complicated course with the involvement of other organ systems. Myocarditis is reported as a complication but the incidence has greatly fallen ever since the development of the mumps vaccine. A child presented to our department with parotid swelling and fever. Persistent tachycardia with irregular pulse led to further cardiac work up which showed decreased ejection fraction and raised serum cardiac enzymes, indicating myocardial damage. With ionotropic agents and supportive care, there was complete normalization of ejection fraction and serum cardiac enzyme levels. He was discharged within a week of admission. This case highlights the importance of suspecting myocarditis in the setting of mumps, a diagnosis that precludes early suspicion in mumps patients suffering from cardiac symptoms not explained by other potential aetiologies. Early suspicion and timely supportive care are essential to ensure favourable outcomes.

Management of Idiopathic Clubfoot by Ponseti Technique in Children Presenting After One Year of Age.

We conducted a study to determine the effectiveness of the Ponseti technique in the management of idiopathic congenital clubfoot in patients older than 1 year of age. A total of 19 patients with 28 clubfeet (16 males [84.2%], 3 females [15.8%]) were included in the present study. The mean age at presentation was 2.7 (range 1 to 3.5) years. The results of treatment using the Ponseti technique were evaluated using the Pirani and Dimeglio scoring systems. The mean precorrection total Pirani score was 4.84 (range 3.5 to 5.5) and the mean precorrection Dimeglio score was 12.96 (range 10 to 14). The mean postcorrection total Pirani score was 0.55 (range 0 to 1), and the mean postcorrection Dimeglio score was 2.32 (range 2 to 3). These differences were statistically significant (p < .001 and p < .001, respectively). In 92.8% of the feet, satisfactory correction of the deformity was achieved. The mean number of casts applied was 8 (range 5 to 12). All but 1 (3.6%) of the clubfeet required tenotomy to achieve correction. The mean follow-up duration was 2.7 (range 1.5 to 3.5) years. We have concluded that the Ponseti technique is an effective method for the management of idiopathic congenital clubfoot, even in toddlers.