Engineered urolithin A-laden functional polymer-lipid hybrid nanoparticles prevent cisplatin-induced proximal tubular injury in vitro.

Functional polymer-lipid hybrid nanoparticles (H-NPs) are a promising class of nanocarriers that combine the benefits of polymer and lipid nanoparticles, offering biocompatibility, structural stability, high loading capacity, and, most importantly, superior surface functionalization. Here, we report the synthesis and design of highly functional H-NPs with specificity toward the transferrin receptor (TfR), using a small molecule ligand, gambogic acid (GA). A fluorescence study revealed the molecular orientation of H-NPs, where the lipid-dense core is surrounded by a polymer exterior, functionalized with GA. Urolithin A, an immunomodulator and anti-inflammatory agent, served as a model drug-like compound to prepare H-NPs via traditional emulsion-based techniques, where H-NPs led to smaller particles (132 nm) and superior entrapment efficiencies (70 % at 10 % drug loading) compared to GA-conjugated polymeric nanoparticles (P-NPs) (157 nm and 52 % entrapment efficiency) and solid lipid nanoparticles (L-NPs) (186 nm and 29 % entrapment efficiency). H-NPs showed superior intracellular accumulation compared to individual NPs using human small intestinal epithelial (FHs 74) cells. The in vitro efficacy was demonstrated by flow cytometry analysis, in which UA-laden H-NPs showed excellent anti-inflammatory properties in cisplatin-induced injury in healthy human proximal tubular cell (HK2) model by decreasing the TLR4, NF-κß, and IL-ß expression. This preliminary work highlights the potential of H-NPs as a novel functional polymer-lipid drug delivery system, establishing the foundation for future research on its therapeutic potential in addressing chemotherapy-induced acute kidney injury in cancer patients.

Low-dose propofol as a solo agent for sedation in postoperative ventilated liver transplant recipients: A preliminary observational study.

Background and Aims: Propofol is a commonly used sedative agent, in a dose of 1.5-4.5 mg.kg-1.h-1. Following liver transplantation (LT), drug metabolism may be altered due to liver mass, altered hepatic blood flow, reduced levels of serum proteins, and liver regeneration. Thus, we hypothesized that propofol requirements in this group of patients would be different as compared to the standard dose. This study evaluated the dose of propofol used for sedation in electively ventilated living donor liver transplantation (LDLT) recipients. Material and Methods: After patients were shifted to the postoperative intensive care unit (ICU) following LDLT surgery, propofol infusion was started at a dose of 1 mg.kg-1.h-1 and titrated to maintain a bispectral index (BIS) value of 60-80. No other sedatives such as opioids or benzodiazepines were used. Dose of propofol, noradrenaline, and arterial lactate levels were noted 2 hourly. Results: The mean propofol dose required in these patients was 1.02 ± 0.26 mg.kg-1.h-1. Noradrenaline was gradually tapered off and stopped within 14 h of shifting to ICU. The mean duration between the time of cessation of propofol infusion till extubation was 2.06 ± 1.44 h. Propofol dose did not correlate with respective lactate levels, ammonia levels, or graft-to-recipient weight ratio. Conclusion: The dose range of propofol required for postoperative sedation in LDLT recipients was lower than the conventional dose.

Signaling pathways and their potential therapeutic utility in esophageal squamous cell carcinoma.

Esophageal cancer is a complex gastrointestinal malignancy with an extremely poor outcome. Approximately 80% of cases of this malignancy in Asian countries including India are of squamous cell origin, termed Esophageal Squamous Cell Carcinoma (ESCC).The five-year survival rate in ESCC patients is less than 20%. Neo-adjuvant chemo-radiotherapy (NACRT) followed by surgical resection remains the major therapeutic strategy for patients with operable ESCC. However, resistance to NACRT and local recurrence after initial treatment are the leading cause of dismal outcomes in these patients. Therefore, an alternative strategy to promote response to the therapy and reduce the post-operative disease recurrence is highly needed. At the molecular level, wide variations have been observed in tumor characteristics among different populations, nevertheless, several common molecular features have been identified which orchestrate disease progression and clinical outcome in the malignancy. Therefore, determination of candidate molecular pathways for targeted therapy remains the mainstream idea of focus in ESCC research. In this review, we have discussed the key signaling pathways associated with ESCC, i.e., Notch, Wnt, and Nrf2 pathways, and their crosstalk during disease progression. We further discuss the recent developments of novel agents to target these pathways in the context of targeted cancer therapy. In-depth research of the signaling pathways, gene signatures, and a combinatorial approach may help in discovering targeted therapy for ESCC.

COVID-19 and tobacco cessation: lessons from India.

OBJECTIVES: The Government of India prohibited the sale of tobacco products during the COVID-19 lockdown to prevent the spread of the SARS-CoV-2 virus. This study assessed the tobacco cessation behaviour and its predictors among adult tobacco users during the initial COVID-19 lockdown period in India. METHODS: A cross-sectional study was conducted with 801 adult tobacco users (both smoking and smokeless tobacco) in two urban metropolitan cities of India over a 2-month period (July to August 2020). The study assessed complete tobacco cessation and quit attempts during the lockdown period. Logistic and negative binomial regression models were used to study the correlates of tobacco cessation and quit attempts, respectively. RESULTS: In total, 90 (11.3%) tobacco users reported that they had quit using tobacco after the COVID-19 lockdown period. Overall, a median of two quit attempts (interquartile range 0-6) was made by tobacco users. Participants with good knowledge on the harmful effects of tobacco use and COVID-19 were significantly more likely to quit tobacco use (odds ratio [OR] 2.2; 95% confidence interval [CI] 1.2-4.0) and reported more quit attempts (incidence risk ratio 5.7; 95% CI 2.8-11.8) compared to those with poor knowledge. Participants who had access to tobacco products were less likely to quit tobacco use compared to those who had no access (OR 0.3; 95% CI 0.2-0.5]. CONCLUSIONS: Access restrictions and correct knowledge on the harmful effects of tobacco use and COVID-19 can play an important role in creating a conducive environment for tobacco cessation among users.

F13A1 transglutaminase expression in human adipose tissue increases in acquired excess weight and associates with inflammatory status of adipocytes.

OBJECTIVE: F13A1/FXIII-A transglutaminase has been linked to adipogenesis in cells and to obesity in humans and mice, however, its role and associated molecular pathways in human acquired excess weight have not been explored. METHODS: We examined F13A1 expression and association to human weight gain in weight-discordant monozygotic twins (Heavy-Lean difference (ΔWeight, 16.8 kg ± 7.16 for n = 12). The twin pairs were examined for body composition (by dual-energy X-ray absorptiometry), abdominal body fat distribution (by magnetic resonance imaging), liver fat content (by magnetic resonance spectroscopy), circulating adipocytokines, leptin and adiponectin, as well as serum lipids. Affymetrix full transcriptome mRNA analysis was performed from adipose tissue and adipocyte-enriched fractions from subcutaneous abdominal adipose tissue biopsies. F13A1 differential expression between the heavy and lean co-twins was examined and its correlation transcriptome changes between co-twins were performed. RESULTS: F13A1 mRNA showed significant increase in adipose tissue (p < 0.0001) and an adipocyte-enriched fraction (p = 0.0012) of the heavier co-twin. F13A1 differential expression in adipose tissue (Heavy-Lean ΔF13A1) showed significant negative correlation with circulating adiponectin (p = 0.0195) and a positive correlation with ΔWeight (p = 0.034), ΔBodyFat (0.044) and ΔAdipocyte size (volume, p = 0.012;) in adipocyte-enriched fraction. A whole transcriptome-wide association study (TWAS) on ΔF13A1 vs weight-correlated ΔTranscriptome identified 182 F13A1-associated genes (r > 0.7, p = 0.05) with functions in several biological pathways including cell stress, inflammatory response, activation of cells/leukocytes, angiogenesis and extracellular matrix remodeling. F13A1 did not associate with liver fat accumulation. CONCLUSIONS: F13A1 levels in adipose tissue increase with acquired excess weight and associate with pro-inflammatory, cell stress and tissue remodeling pathways. This supports its role in expansion and inflammation of adipose tissue in obesity.

Next-Generation Noncompetitive Nanosystems Based on Gambogic Acid: In silico Identification of Transferrin Receptor Binding Sites, Regulatory Shelf Stability, and Their Preliminary Safety in Healthy Rodents.

A major challenge in drug delivery is to enhance the transport of drugs across biological barriers, such as the small intestine, the blood-brain barrier, and the blood-retinal/ocular barrier, and to effectively reach the site of action while minimizing the systemic impact. In recent years, piggybacking cell surface receptors have been considered a viable strategy for active drug delivery across the biological barriers. However, the ligands used to target drugs to plasma membrane receptors often have to compete against endogenous ligands, thereby limiting their binding to the cell surface and their transport across barriers. To address this problem, gambogic acid (GA) was identified as a noncompetitive ligand specific to the transferrin receptor (TfR), a receptor present on various barriers. However, the binding sites of the GA on TfR remain unknown, an essential step toward establishing structure-activity relationships. In silico binding site prediction tools, blind docking, and molecular docking simulation confirm that the GA binding site on the TfR is independent of the transferrin-bound iron binding sites. The GA-conjugated polyesters were processed into nanoparticles suitable for drug delivery applications that possess excellent storage stability under regulatory conditions. Traditionally, GA has been used as an anticancer compound that warrants safety assessment. The preliminary studies in healthy rodents on 10-repeated oral doses show no adverse effects. This work will generate paradigm shifting, new knowledge in the field of nanomedicines using unique noncompetitive nanosystems that do not compete with endogenous transferrin.

Polyester Nanoparticle Encapsulation Mitigates Paclitaxel-Induced Peripheral Neuropathy.

Chemotherapy utilizing cytotoxic drugs, such as paclitaxel (PTX), is still a commonly used therapeutic approach to treat both localized and metastasized cancers. Unlike traditional regimens in which PTX is administered at the maximum tolerated dose, alternative regimens like metronomic dosing are beneficial by administering PTX more frequently and in much lower doses exploiting antiangiogenic and immunomodulatory effects. However, PTX-induced peripheral neuropathy and lack of patient compliant dosage forms of PTX are major roadblocks for the successful implementation of metronomic regimens. Because of the success of polyester nanoparticle drug delivery, we explored the potential of nanoparticle-encapsulated paclitaxel (nPTX) in alleviating peripheral neuropathy using a rat model. Rats were injected intraperitoneally with 2 mg/kg body weight of PTX or nPTX on four alternate days, and neuropathic pain and neuronal damage were characterized using behavioral assessments, histology, and immunohistochemistry. The reduction in tactile and nociceptive pressure thresholds was significantly less in nPTX-treated rats than in PTX-treated rats over a 16-day study period. Histological analysis showed that the degree of dorsal root ganglion (DRG) degeneration and reduction in motor neurons in the spinal cord was significantly lower in the nPTX group than the PTX group. Further, immunofluorescence data reveals that nPTX-treated rats had an increased density of a neuronal marker, ß-tubulin-III, reduced TUNEL positive cells, and increased high molecular weight neurofilament in the spinal cord, DRG, and sciatic nerves compared with PTX-treated rats. Therefore, this work has important implications in improving risk-benefit profile of PTX, paving the way for metronomic regimens.

Evolving concepts in prognostic scoring of chronic GvHD.

Chronic GvHD (cGvHD) remains one of the most complex and challenging complications after allogeneic hematopoietic cell transplantation. Emerging knowledge about the clinical manifestations and associated organ involvement of cGvHD has led to the establishment of prognostic parameters for post-transplant survival among affected allograft recipients. Studies employing the pre-National Institutes of Health (NIH) consensus data on cGvHD incidence and its risks have led to development of the CIBMTR's cGvHD risk stratification, which serves as the most refined and validated prognostic tool for estimating survival of patients with cGvHD. However, cGvHD global severity scoring has recently evolved as a powerful prognostic tool for patient survival in the post-NIH consensus era. Current use of the substantially redefined NIH criteria of cGvHD diagnosis and measurements of its severity makes it challenging to interpret prognostic scoring systems generated in the pre-NIH era. Some of the pre-NIH prognostic parameters, however, appear to retain their significance in predicting survival independently from the NIH global severity score. Thus, future analyses of prospective cohorts of patients with cGvHD defined by NIH consensus criteria will be critical in reconciling and integrating various prognostic scoring systems of cGvHD.

GvHD after umbilical cord blood transplantation for acute leukemia: an analysis of risk factors and effect on outcomes.

Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, we analyzed 1404 umbilical cord blood transplantation (UCBT) patients (single (<18 years)=810, double (⩾18 years)=594) with acute leukemia to define the incidence of acute GvHD (aGvHD) and chronic GvHD (cGvHD), analyze clinical risk factors and investigate outcomes. After single UCBT, 100-day incidence of grade II-IV aGvHD was 39% (95% confidence interval (CI), 36-43%), grade III-IV aGvHD was 18% (95% CI, 15-20%) and 1-year cGvHD was 27% (95% CI, 24-30%). After double UCBT, 100-day incidence of grade II-IV aGvHD was 45% (95% CI, 41-49%), grade III-IV aGvHD was 22% (95% CI, 19-26%) and 1-year cGvHD was 26% (95% CI, 22-29%). For single UCBT, multivariate analysis showed that absence of antithymocyte globulin (ATG) was associated with aGvHD, whereas prior aGvHD was associated with cGvHD. For double UCBT, absence of ATG and myeloablative conditioning were associated with aGvHD, whereas prior aGvHD predicted for cGvHD. Grade III-IV aGvHD led to worse survival, whereas cGvHD had no significant effect on disease-free or overall survival. GvHD is prevalent after UCBT with severe aGvHD leading to higher mortality. Future research in UCBT should prioritize prevention of GvHD.

Autologous bone marrow cell transplantation in acute spinal cord injury--an Indian pilot study.

STUDY DESIGN: Phase- I/II, prospective, randomized, single-blind, controlled pilot study. PRIMARY OBJECTIVE: To determine the safety and feasibility of autologous bone marrow transplantation in patients with acute spinal cord injury (SCI) via two routes of transplantation as compared with controls. SETTING: Indian Spinal Injuries Center, New Delhi. METHODS: Twenty-one subjects with acute, American Spinal Injury Association Impairment Scale (AIS) A (complete), traumatic SCI with neurological level T1-T12, were recruited and randomized into three groups of seven subjects each. Two groups underwent cell transplantation through the intrathecal or intralesional route, whereas the third served as control. Participants were assessed at baseline and followed up at 6 months and 12-months post enrollment. Safety and tolerability were evaluated by monitoring for any adverse events. Efficacy was assessed through neurological, functional and psychological evaluation, as well as through electrophysiological studies and urodynamics. RESULTS: Surgery was tolerated well by all participants. There were no significant adverse events attributable to the procedure. There was no significant improvement in the neurological, electrophysiological or urodynamic efficacy variables. A statistically significant improvement in functional scores as evaluated by the Spinal Cord Independence Measure and International Spinal Cord Injury Scale was observed in all groups. CONCLUSIONS: The procedure is safe and feasible in AIS A participants with thoracic-level injuries at 12-months follow-up. No efficacy could be demonstrated that could be attributed to the procedure.

Oral chronic GVHD outcomes and resource utilization: a subanalysis from the chronic GVHD consortium.

OBJECTIVES: This study evaluated the extent to which oral chronic graft-versus-host disease (cGVHD) consensus assessments are predictive of management across institutions with and without oral medicine (OM) centers, and whether ancillary care guidelines are followed within clinical practice. METHODS: Longitudinal oral cGVHD data were abstracted from the cGVHD Consortium, and additional mouth-specific management data were analyzed across five transplant centers. RESULTS: Seventy-nine patients with 656 visits were observed for a median of 7.1 months with one visit per follow-up month. Ancillary therapies for oral cGVHD were prescribed for 67% of patients for a median of 0.46 months (per follow-up month) at OM centers and 0.78 months at non-OM centers. Patients treated with ancillary therapy were more likely to have an National Institutes of Health (NIH) mouth score of ≥1 (P < 0.001, odds ratio: 5.1) and mouth pain (P = 0.01, odds ratio: 2.6). The odds ratios of receiving ancillary therapy from OM experts were higher than transplant physicians (53%; P = 0.03). CONCLUSIONS: Oral cGVHD consensus assessments corresponding with ancillary therapy use were mouth pain and NIH mouth score, with higher odds ratios of receiving therapy from OM experts. Ancillary care guidelines for oral cGVHD are reflected in academic clinical practice with respect to utilization of recommended prescriptions.

MALT1 induced immune response is governed by miR-2909 RNomics.

The paracaspase mucosa-associated lymphoid tissue 1 (MALT1) has been widely recognized to play crucial role in lymphocyte activation, development and the generation of lymphomas through the modulation of innate and adaptive immune responses. Our results reported here provide evidence for the first time to support the view that MALT1 exerts its effect upon immune response involving genes coding for retinoic acid-inducible gene 1 (RIG1); interferon-ß (IFN-ß); apo-lipoprotein B mRNA-editing, enzyme-catalytic, polypeptide-like 3G (APOBEC3G); IFN-γ; chemokine (C-C motif) ligand 5 (CCL5) and interleukin-17 (IL-17) through the initiation of cellular miR-2909 RNomics. This ensures sustained expression of specificity protein 1 (SP1)-dependent regulation of genes that in-turn governs MALT1 induced immune response. Based upon these results, a mechanistic-pathway is proposed that links the epigenomic-interplay between MALT1 and miR-2909.

Taxation of smokeless tobacco in India.

BACKGROUND: The role of fiscal policy, especially taxation, though has been proved to be an effective instrument of tobacco control, its application is limited in India due to several reasons. This paper examines the tax structure, price and affordability of SLT products in order to provide evidence on how to strengthen the role of fiscal policy in tobacco control. METHOD: Secondary data on tax structure and revenue from tobacco products were collected from the Ministry of Finance, Government of India. In order to measure the rise of prices corresponding to the increase in tax rate, the retail price index (RPI) and Whole Price Index (WPI) of SLT products were compared with the price index for all commodities for the period 2006-2012. The affordability of tobacco products is calculated by dividing prices of tobacco products by per capita income. RESULTS: During the last 6 years, the tax rate on SLT has gone up leading to a rise in the prices of SLT products more than the general price rise. However, the price rise is less than the per capita income growth indicating increasing affordability. The study observed a decline in the consumption of zarda and kahini due to the price increase during 2008-2013. However, the decline in the consumption of zarda is less compared with khaini due to a very low rise in its price. CONCLUSION: The prices should be raised more than the growth in income to influence consumption. Tax administration is a major challenge for SLT products and strengthening it could enhance revenue collection from SLT products.

The effect of equine antithymocyte globulin on the outcomes of reduced intensity conditioning for AML.

Whether or not the benefits of antithymocyte globulin (ATG) on engraftment and GVHD are offset by increased risk of relapse, delayed T-cell recovery and increased infections remains controversial. We retrospectively studied the effect of ATG in 144 AML patients, 34 of whom received ATG, undergoing reduced intensity conditioning (RIC) umbilical cord blood transplantation (UCB) or HLA-matched sibling PBSC. ATG patients had not received intensive chemotherapy for 3 months before transplantation for UCB, 6 months for PBSC. There were no differences in engraftment between ATG and non-ATG patients. The cumulative incidences of TRM as well as acute and chronic GVHD in ATG-treated patients were not statistically different. ATG patients had significantly more infections between 46 and 180 days post transplantation. Unexpectedly, after adjusting for donor type, relapse was lower among ATG recipients (relative risk (RR) 0.5, 95% confidence interval (CI) 0.3-1.0, P=0.04). In summary, administration of ATG to AML patients undergoing RIC had no adverse impact on major clinical outcomes. ATG may be indicated for patients at higher risk of graft failure after allogeneic hematopoietic cell transplantation (allo-HCT).

A workplace colorectal cancer screening program in firefighters: lessons learned.

BACKGROUND: Although colorectal cancer (CRC) screening is widely recommended, screening rates remain low. Workplace interventions have the potential to increase rates of screening. AIMS: To evaluate the impact of a workplace CRC screening program targeting active duty and retired firefighters. METHODS: A letter, a fecal immunochemical test (FIT) kit and a survey were mailed to all active duty and retired San Francisco firefighters aged 40 and older during 2008-09. The survey included questions about CRC risk factors and prior CRC screening tests. The primary outcome was return of the completed FIT. RESULTS: FIT kits and surveys were sent to 1203 firefighters. In total, 445 individuals (37%) completed the survey, and 400 (33%) completed the FIT. Forty-five per cent of respondents had had a stool test for blood at some time, although few (8%) had had it within the past year. Thirty-six per cent of respondents said they had had a sigmoidoscopy at some time, although only 15% had had it within the past 5 years and 37% within the past 10 years. Among those aged 50 and older, 59% had had a test for colon cancer at some time. CONCLUSIONS: A workplace intervention can increase CRC screening rates in firefighters. Future studies should focus on the long-term sustainability of this type of program.

Adenosine induced coronary spasm - a rare presentation.

Adenosine is commonly used as a pharmacological agent in myocardial perfusion imaging, as an antiarrhythmic agent, and in Cath Lab. during PCI for treating no reflow phenomenon. Coronary spasm has been reported following adenosine injection during stress imaging. We report a rare complication with ST segment elevation, following adenosine injection, given for treatment of supraventricular tachycardia.

Single-stage laparoscopic common bile duct exploration and cholecystectomy versus two-stage endoscopic stone extraction followed by laparoscopic cholecystectomy for patients with concomitant gallbladder stones and common bile duct stones: a randomized controlled trial.

BACKGROUND: The ideal method for managing concomitant gallbladder stones and common bile duct (CBD) stones is debatable. The currently preferred method is two-stage endoscopic stone extraction followed by laparoscopic cholecystectomy (LC). This prospective randomized trial compared the success and cost effectiveness of single- and two-stage management of patients with concomitant gallbladder and CBD stones. METHODS: Consecutive patients with concomitant gallbladder and CBD stones were randomized to either single-stage laparoscopic CBD exploration and cholecystectomy (group 1) or endoscopic retrograde cholangiopancreatography (ERCP) for endoscopic extraction of CBD stones followed by LC (group 2). Success was defined as complete clearance of CBD and cholecystectomy by the intended method. Cost effectiveness was measured using the incremental cost-effectiveness ratio. Intention-to-treat analysis was performed to compare outcomes. RESULTS: From February 2009 to October 2012, 168 patients were randomized: 84 to the single-stage procedure (group 1) and 84 to the two-stage procedure (group 2). Both groups were matched with regard to demographic and clinical parameters. The success rates of laparoscopic CBD exploration and ERCP for clearance of CBD were similar (91.7 vs. 88.1 %). The overall success rate also was comparable: 88.1 % in group 1 and 79.8 % in group 2 (p = 0.20). Direct choledochotomy was performed in 83 of the 84 patients. The mean operative time was significantly longer in group 1 (135.7 ± 36.6 vs. 72.4 ± 27.6 min; p ≤ 0.001), but the overall hospital stay was significantly shorter (4.6 ± 2.4 vs. 5.3 ± 6.2 days; p = 0.03). Group 2 had a significantly greater number of procedures per patient (p < 0.001) and a higher cost (p = 0.002). The two groups did not differ significantly in terms of postoperative wound infection rates or major complications. CONCLUSIONS: Single- and two-stage management for uncomplicated concomitant gallbladder and CBD stones had similar success and complication rates, but the single-stage strategy was better in terms of shorter hospital stay, need for fewer procedures, and cost effectiveness.

Higher therapeutic CsA levels early post transplantation reduce risk of acute GVHD and improves survival.

We studied whether early CsA trough levels were associated with the risk of acute GVHD in 337 patients after either sibling PBSC or double umbilical cord blood transplantation. All patients, regardless of donor type, started CsA at a dose of 5 mg/kg i.v. divided twice daily, targeting trough concentrations 200-400 ng/mL. The CsA level was studied by a weighted average method calculated by giving 70% of the weight to the level that was measured just before the onset of the event or day +30. We found that higher weighted average CsA trough levels early post transplantation contributed to lower risk of acute GVHD, and lower non-relapse and overall mortality. Thus, our data support close monitoring with active adjustments of CsA dosing to maintain therapeutic CsA levels in the first weeks of allo-HCT. In patients who are near or even modestly above the CsA target trough level, in the absence of CsA-related toxicity, dose reduction should be cautious to avoid subtherapeutic drug levels resulting in higher risk of acute GVHD.