Results of the First Clinical Study in Humans That Combines Hyperbaric Oxygen Pretreatment with Autologous Peripheral Blood Stem Cell Transplantation.

Patients undergoing high-dose chemotherapy and autologous hematopoietic cell transplantation (auto-HCT) are at risk for multiple morbidities, including mucosal inflammation and neutropenic fever, both related to neutropenia. Evidence from our preclinical work in an umbilical cord blood (UCB) transplantation murine model suggests that treatment with hyperbaric oxygen (HBO) before UCB infusion improves UCB CD34+ cell engraftment by reducing erythropoietin levels. A pilot clinical trial using HBO in patients undergoing UCB transplantation showed improvement in kinetics of blood count recovery. In this study, we evaluated HBO in combination with auto-HCT. Our primary aim was to determine the safety of HBO in this setting and secondarily to determine its efficacy in reducing time to neutrophil and platelet engraftment compared with matched historic controls. Patients with multiple myeloma, non-Hodgkin lymphoma, and Hodgkin disease eligible for auto-HCT were included. On day 0, patients received HBO treatment consisting of exposure to 2.5 atmosphere absolutes for a total of 90 minutes, in a monoplace hyperbaric chamber, breathing 100% oxygen. Six hours after the start of HBO, peripherally mobilized stem/progenitor cells were infused and patients were followed daily for toxicity and blood count recovery. All patients received daily granulocyte colony-stimulating factor starting on day +5 and until absolute neutrophil count (ANC) of ≥1500 or ANC of 500 for 3 consecutive days. A matched historic cohort of 225 patients who received auto-HCT between January 2008 and December 2012 was chosen for comparison and matched on sex, age, conditioning regimen, and disease type. We screened 26 patients for this study; 20 were treated and included in the primary analysis, and 19 completed the HBO therapy and were included in the secondary analysis. Although the median time to neutrophil count recovery was 11 days in both the HBO and control cohorts, the Kaplan-Meier estimates of the full distributions indicate that the time to neutrophil recovery was generally about 1 day sooner for HBO versus historical controls (log-rank P = .005; range, 9 to 13 for HBO patients and 7 to 18 for controls). The median time to platelet count recovery was 16 days (range, 14 to 21) for HBO versus 18 days (range, 11 to 86) for controls (log-rank P < .0001). In the secondary analysis comparing the HBO cohort who completed HBO therapy (n = 19) with our historical cohort, we evaluated neutropenic fever, growth factor use, mucositis, day +100 disease responses, and blood product use. HBO was associated with less growth factor use (median 6 days in HBO cohort versus median 8 days in controls, P < .0001). Packed RBC and platelet transfusion requirements were not statistically different between the 2 cohorts. Mucositis incidence was significantly lower in the HBO cohort (26.3% in HBO cohort versus 64.2% in controls, P = .002). HBO therapy appears to be well tolerated in the setting of high-dose therapy and auto-HCT. Prospective studies are needed to confirm potential benefits of HBO with respect to earlier blood count recovery, reduced mucositis, and growth factor use, and a cost-benefit analysis is warranted. © 2019 American Society for Blood and Marrow Transplantation.

Correlates of diabetic retinopathy: A case study.

Prevalence of diabetes mellitus is increasing worldwide particularly in developing countries as according to International Diabetes Federation, globally a rise from 451 million diabetic people in 2017 to 693 million in 2045 is expected. Diabetic retinopathy is one of the major consequences of diabetes mellitus, so knowing its risk factors can be very helpful. For identifying the risk factors of the Diabetic Retinopathy (DR) in Faisalabad and to determine whether DR is more caused by type 1 or type 2 diabetes, a cross-sectional study was conducted at major hospitals in Faisalabad district during February-July 2016. Descriptive statistics were used for initial screening of the significant variables. Then binary logistic regression was applied to measure the influence of different factors on likelihood of DR. Using Odds Ratio (OR) from logistic regression as measure of influence, the problem of DR was found to be higher among males (OR=1.913; 95% C.I, 1.072~3.413), married patients (OR=5.678; 95% C.I=2.206~14.616), patients with type 1 diabetes (OR=2.195; 95% C.I=1.205~3.997), patients with obesity (OR=25.736; 95% C.I=11.033~60.031), patients using insulin treatment (OR=6.678; 95% C.I=2.330~10.138). The study demonstrated a high prevalence of DR in Faisalabad. Eye examination, social status of patients and duration of diabetes were also found as significant variables affecting DR.

Risk factors of neonatal mortality in Faisalabad, Pakistan.

The objective of study was to find out major correlates of neonatal mortality. The main focus was in determining the impact of different demographic and health related characteristics of neonates and their mothers. A planned questionnaire was prepared in order to collect the information from mothers of newborns. The data were collected from different public and private hospitals of Faisalabad district. Discharge condition of neonate (dead or alive) was taken as response. Binary logistic regression was applied in order to unveil the impact of different contributory factors on the chances of neonatal mortality. Marriage age of mother, age of mother at baby birth, number of pregnancies, time since last birth, antenatal care, delivery mode, gender of baby, baby weight, baby disease and its nature, domestic violence, baby nutrition and residence were found to be significant factors affecting neonatal mortality. Odds ratio was used as a measure of association. From the results, it can be summed up that marriages at optimal ages, lesser frequency of pregnancies, early initiation of mother feeding, increased care during pregnancy to avoid low birth weight and birth time diseases, and increased facilities of antenatal care in rural areas can effectively reduce the neonatal mortality rates.

Characterization of a salt resistant bacterial strain Proteus sp. NA6 capable of decolorizing reactive dyes in presence of multi-metal stress.

Microbial biotechnologies for the decolorization of textile wastewaters have attracted worldwide attention because of their economic suitability and easiness in handling. However, the presence of high amounts of salts and metal ions in textile wastewaters adversely affects the decolorization efficiency of the microbial bioresources. In this regard, the present study was conducted to isolate salt tolerant bacterial strains which might have the potential to decolorize azo dyes even in the presence of multi-metal ion mixtures. Out of the tested 48 bacteria that were isolated from an effluent drain, the strain NA6 was found relatively more efficient in decolorizing the reactive yellow-2 (RY2) dye in the presence of 50 g L(-1) NaCl. Based on the similarity of its 16S rRNA gene sequence and its position in a phylogenetic tree, this strain was designated as Proteus sp. NA6. The strain NA6 showed efficient decolorization (>90 %) of RY2 at pH 7.5 in the presence of 50 g L(-1) NaCl under static incubation at 30 °C. This strain also had the potential to efficiently decolorize other structurally related azo dyes in the presence of 50 g L(-1) NaCl. Moreover, Proteus sp. NA6 was found to resist the presence of different metal ions (Co(+2), Cr(+6), Zn(+2), Pb(+2), Cu(+2), Cd(+2)) and was capable of decolorizing reactive dyes in the presence of different levels of the mixtures of these metal ions along with 50 g L(-1) NaCl. Based on the findings of this study, it can be suggested that Proteus sp. NA6 might serve as a potential bioresource for the biotechnologies involving bioremediation of textile wastewaters containing the metal ions and salts.

Stem Cell Origin of Cancer: Clinical Implications beyond Immunotherapy for Drug versus Therapy Development in Cancer Care.

Although immunotherapy has revolutionized cancer care, there is still an urgent need to enhance its efficacy and ensure its safety. A correct cancer theory and proper scientific method empower pertinent cancer research and enable effective and efficient drug versus therapy development for patient care. In this perspective, we revisit the concept of immune privilege in a cancer cell versus normal cell, as well as in a cancer stem cell versus normal stem cell. We re-examine whether effective immunotherapies are efficacious due to their anti-cancer and/or immune modulatory mechanisms. We reassess why checkpoint inhibitors (CPIs) are not equal. We reconsider whether one can attribute the utility of immunotherapy to specific cancer subtypes and its futility to certain tumor/immune compartments, components, and microenvironments. We propose ways and means to advance immunotherapy beyond CPIs by combining anti-PD1/L1 with various other treatment modalities according to an appropriate scientific theory, e.g., stem cell origin of cancer, and based on available clinical evidence, e.g., randomized clinical trials. We predict that a stem cell theory of cancer will facilitate the design of better and safer immunotherapy with improved selection of its use for the right patient with the right cancer type at the right time to optimize clinical benefits and minimize potential toxic effects and complications.

Real-World Survival of First-Line Immune Checkpoint Inhibitor Treatment Versus Chemotherapy in Older Patients With Non-Small-Cell Lung Cancer and Synchronous Brain Metastases.

PURPOSE: This study assessed real-world survival among older patients with non-small-cell lung cancer (NSCLC) and brain metastases (BMs) at diagnosis (synchronous BM [SBM]) receiving first-line immune checkpoint inhibitors (ICIs) compared with chemotherapy only. METHODS: Patients with NSCLC and SBM age 65 years or older at diagnosis from 2010 to 2019 SEER-Medicare database and received US Food and Drug Administration-approved ICIs (pembrolizumab/nivolumab/ipilimumab/atezolizumab/durvalumab/cemiplimab) and/or chemotherapy (platinum-based doublets/taxane/pemetrexed/gemcitabine) as first-line systemic treatment were included, excluding those with no cranial radiation or ever being treated with targeted therapies. Overall survival time was from the start of systemic treatment (ICI/chemotherapy) to death, censored at disenrollment from Medicare part A/B, enrollment in part C, or end of the study period (December 31, 2019). Kaplan-Meier (KM) survival curves were compared between treatment groups using the log-rank test. Multivariable Cox proportional hazards (CPH) model was used to estimate hazard ratio (HR) between groups, adjusting for patients' sociodemographic and clinical characteristics. RESULTS: The study included 1,481 patients (1,303 chemotherapy and 178 ICI). The median (range) age was 71 (65-91) years. First-line ICI patients were more likely to be older, live in urban areas, and less likely to be non-White than the chemotherapy group. KM estimates showed that survival curves initially overlapped but diverged approximately 6 months after initiating first-line systemic treatment (median survival [95% CI]: ICI, 190 [131 to 303] days versus chemotherapy, 189 [177 to 201] days), with ICI showing a better survival than the chemotherapy group (log-rank test P < .0001). First-line ICI was associated with a lower risk of death compared with chemotherapy in adjusted CPH model (HR [95% CI], 0.67 [0.55 to 0.80]; P < .0001). CONCLUSION: Among older patients with NSCLC and SBM, first-line ICI use was associated with improved survival occurring 6 months after treatment initiation compared with chemotherapy only.

Immune Checkpoint Inhibitors-Associated Cardiotoxicity.

Large population-based studies examining differences in ICI-associated cardiotoxicity across cancer types and agents are limited. Data of 5518 cancer patients who received at least one cycle of ICIs were extracted from a large network of health care organizations. ICI treatment groups were classified by the first ICI agent(s) (ipilimumab, nivolumab, pembrolizumab, cemiplimab, avelumab, atezolizumab, or durvalumab) or its class (PD-1 inhibitors, PD-L1 inhibitors, CTLA4-inhibitors, or their combination (ipilimumab + nivolumab)). Time to first cardiac adverse event (CAE) (arrhythmia, acute myocardial infarction, myocarditis, cardiomyopathy, or pericarditis) developed within one year after ICI initiation was analyzed using a competing-risks regression model adjusting for ICI treatment groups, patient demographic and clinical characteristics, and cancer sites. By month 12, 12.5% developed cardiotoxicity. The most common cardiotoxicity was arrhythmia (9.3%) and 2.1% developed myocarditis. After adjusting for patient characteristics and cancer sites, patients who initiated on monotherapy with ipilimumab (adjusted Hazard Ratio (aHR): 2.00; 95% CI: 1.49−2.70; p < 0.001) or pembrolizumab (aHR: 1.21; 95% CI: 1.01−1.46; p = 0.040) had a higher risk of developing CAEs within one year compared to nivolumab monotherapy. Ipilimumab and pembrolizumab use may increase the risk of cardiotoxicity compared to other agents. Avelumab also estimated a highly elevated risk (aHR: 1.92; 95% CI: 0.85−4.34; p = 0.117) compared to nivolumab and other PD-L1 agents, although the estimate did not reach statistical significance, warranting future studies.

Stem Cell Theory of Cancer: Implications for Translational Research from Bedside to Bench.

A stem cell theory of cancer considers genetic makeup in the proper cellular context. It is a unified theory of cancer that unites the genome with the epigenome, links the intracellular with the extracellular, and connects the cellular constituents and compartments with the microenvironment. Although it allies with genomic medicine, it is better aligned with integrated medicine. In this perspective, we focus on translational research in cancer care. We expose some intrinsic fallacies in translational research when it relates to the basic principles of the scientific method in the care of patients with genomic medicine versus integrated medicine. We postulate that genomic medicine may be at the root of many failed efforts in drug development and data reproducibility. We propose an alternate heuristic approach that may expedite the development of safe and effective treatments and minimize the generation of unproductive pharmaceutical products and nonreproducible experimental results. Importantly, a heuristic approach emphasizes the role of a pertinent scientific theory and distinguishes therapy development from drug development, such that we discover not only useful drugs but also better ways to use them in order to optimize patient care and maximize clinical outcomes.

Photoinduced Fabrication of Zinc Oxide Nanoparticles: Transformation of Morphological and Biological Response on Light Irradiance.

The photoinduced synthesis of zinc oxide nanoparticles (ZnO NPs) was carried out to unveil the effects of change in wavelength of photons. ZnO NPs were synthesized by the coprecipitation technique exposed to different light regimes [dark environment, daylight, and blue-, green-, yellow-, and red-colored light-emitting diodes (LEDs)] at room temperature. X-ray diffractogram (XRD) revealed the wurtzite structure of ZnO NPs. A small change in the size of ZnO NPs (17.11-22.56 nm) was observed with the variation in wavelength of lights from 350 to 700 nm. Spherical to hexagonal disks and rodlike surface morphologies were observed by scanning electron microscopy (SEM). The elemental composition and surface chemistry of NPs were studied by energy-dispersive X-ray diffractive (EDX) and Fourier transform infrared (FTIR) spectra. Maximum free radical quenching activity, cation radical scavenging, and total antioxidant capacity were found in ZnO NPs synthesized under green light (28.78 ± 0.18, 30.05 ± 0.21%, and 36.55 ± 2.63 µg AAE/mg, respectively). Daylight-synthesized NPs (DL-ZNPs) showed the greatest total reducing potential (15.81 ± 0.33 µg AAE/mg) and metal-chelating activity (37.77 ± 0.31%). Photoinduced ZnO NPs showed significant enzyme inhibitory effects on amylase, lipase, and urease by red-light NPs (87.49 ± 0.19%), green-light NPs (91.44 ± 0.29%), and blue-light NPs (92.17 ± 0.34%), respectively. Photoinduced ZnO NPs have been employed as nanozymes and found to exhibit intrinsic peroxidase-like activity as well. Blue-light-synthesized ZnO NPs displayed the strongest antibacterial activity (23 mm) against methicillin-resistant Staphylococcus aureus (MRSA). This study can be considered as a novel step toward the synthetic approach using LEDs to synthesize ZnO NPs with specific physicochemical properties and extends a great prospect in the environmental chemistry, food safety, and biomedical fields as nanozyme, antioxidant, antibacterial, anti-α-amylase, antiurease, and antilipase agents.

Molecular Pathogenesis and Classification of Colorectal Carcinoma.

PURPOSE OF REVIEW: Molecular pathways in colorectal carcinogenesis involve several complex genetic and epigenetic modulations that cause normal colonic mucosa to metamorphose into a benign polyp and subsequently into a malignant tumor. Our purpose is to recapitulate historical and recent genomic research in order to augment the understanding of colorectal cancer pathogenesis. RECENT FINDINGS: In 2015, the molecular classification for colorectal cancers was unified into one system with four distinct groups, also called as consensus molecular subtypes. This led to an enhanced understanding of molecular and immune signatures which has implications on predicting the clinical behavior as well as response to different therapeutic agents. SUMMARY: In this review, we expound on the current literature as well as draw on our own experience to present the important molecular pathogenesis pathways, key genetic mutations, differences in pathogenesis of left versus right sided tumors as well as the molecular classification of colorectal cancers.

Efficient estimation of Pareto model: Some modified percentile estimators.

The article proposes three modified percentile estimators for parameter estimation of the Pareto distribution. These modifications are based on median, geometric mean and expectation of empirical cumulative distribution function of first-order statistic. The proposed modified estimators are compared with traditional percentile estimators through a Monte Carlo simulation for different parameter combinations with varying sample sizes. Performance of different estimators is assessed in terms of total mean square error and total relative deviation. It is determined that modified percentile estimator based on expectation of empirical cumulative distribution function of first-order statistic provides efficient and precise parameter estimates compared to other estimators considered. The simulation results were further confirmed using two real life examples where maximum likelihood and moment estimators were also considered.

Survival analysis of heart failure patients: A case study.

This study was focused on survival analysis of heart failure patients who were admitted to Institute of Cardiology and Allied hospital Faisalabad-Pakistan during April-December (2015). All the patients were aged 40 years or above, having left ventricular systolic dysfunction, belonging to NYHA class III and IV. Cox regression was used to model mortality considering age, ejection fraction, serum creatinine, serum sodium, anemia, platelets, creatinine phosphokinase, blood pressure, gender, diabetes and smoking status as potentially contributing for mortality. Kaplan Meier plot was used to study the general pattern of survival which showed high intensity of mortality in the initial days and then a gradual increase up to the end of study. Martingale residuals were used to assess functional form of variables. Results were validated computing calibration slope and discrimination ability of model via bootstrapping. For graphical prediction of survival probability, a nomogram was constructed. Age, renal dysfunction, blood pressure, ejection fraction and anemia were found as significant risk factors for mortality among heart failure patients.

Epidemiological patterns of suicide terrorism in the civilian Pakistani population.

In this study, we assessed the epidemiological patterns of suicide terrorism in the civilian population of Pakistan. Information about suicide terrorism-related events, deaths and injuries was extracted from the South-Asian Terrorism Portal (SATP) for the period from 2002 to October 2009. Of 198 events, civilians were involved in 194 events. Civilians accounted for 74.1% (N = 2017) of those who died and 93.8% (N = 6129) of those who were injured. In nine districts, mortality rates were more than one death per 100,000 inhabitants per year. The yearly trend showed a shift of attack targets from foreigners and sectarian targets in 2002-2005 to security forces or general public in 2006-2009. Attacks on public installations (mosques) or political gatherings resulted in a significantly greater (P ≤ 0.02) number of deaths (22 vs. 8) and injuries (59 vs. 24) per event compared with security installations. These results show that prevention might focus on political negotiation with armed groups and that appropriate measures should be taken to protect mosques and political gatherings.