Imparting child nutritional assessment skills among medical students using hybrid problem-based learning approach in a community setting.

Background: Malnutrition affects up to a third of children in India, with severe and acute malnutrition prevalent among under five children. Nutritional assessment skills for detecting malnutrition in children in primary care settings are vital. Hybrid problem-based learning (HPBL) is an innovative, collaborative, and adaptable instructional learning strategy that can be used to teach medical students clinical skills in a community setting. Methods: A two-month quasi-experimental study was undertaken in a rural setting with third-year medical students. Faculty members were sensitized and subject experts developed a training module addressing the knowledge, attitude, communication, and practice domains. The students underwent a 3-week training module where pre-testing, case presentation, and group formation in first week, an anchoring lecture, tutorial and self-directed learning and role-play by students in subsequent week, and in last week, case discussion, post-testing, and feedback rounds were done. Results: In all domains, knowledge (3.8, 0.01), practice (4.3, 0.01), attitude and communication (3.7, 0.01), and proportional satisfactory responses, the HPBL approach resulted in a significant improvement in nutritional assessment competency. Teachers preferred the practical and engaging character of the approach, stating that doubts and questions were better addressed and that they would use it to teach similar topics. Conclusion: HPBL is an excellent teaching method for clinical skills, like nutritional assessment in simulated/field settings. The novel teaching-learning approach was well received by students and faculty members. Learning outcomes and satisfaction rates enhanced in students and faculty were encouraged to apply the approach to other topics.

Use of exemplars-based feedforward to improve the performance of medical students in constructed response assessment.

Background: Exemplars are the graded responses to theory questions from previous examinations and are considered as means to guide students about what is valued by assessors; hence giving feed forward to students before the exam and developing self-regulated learning among students. The present study was undertaken to compare the effect on performance of students between intervention (didactic lecture and exemplar) and control group (didactic lecture). Methods: This study was an interventional study conducted among 256 students of a medical college in Rajasthan, India. Participants were randomized to either the control group A or to the interventional group B. Outcomes included a post intervention test evaluating the knowledge gained after the session and students 'attitudes about the same. A focus group discussion was conducted investigating the perceptions. The feedback from faculty was also taken. Results: The mean post test score of intervention group was found to be 6.1 ± 1.74 and of the control group was 5.5 ± 1.6; significantly higher with p-value of 0.03. Out of 128 participants in group B, majority (n = 94,73%) believed that exemplars improve learning and created their interest in topic (n = 78, 60.9%). Most of students (66%) were of the opinion that exemplars should be regularly used with didactic lectures. Key themes identified from focus group were: advantages of the exemplars-based feedforward, challenges in implementation and ways to improve the method. Conclusion: Exemplars improved the performance of students. The faculty members and students agreed that they are an effective tool to enhance learning.

A Multicenter Randomized Controlled Trial Comparing Safety, Efficacy, and Cost-effectiveness of the Surgisis Anal Fistula Plug Versus Surgeon's Preference for Transsphincteric Fistula-in-Ano: The FIAT Trial.

OBJECTIVE: To undertake a randomized comparison of the Biodesign Surgisis anal fistula plug against surgeon's preference in treating cryptoglandular transsphincteric fistula-in-ano. SUMMARY BACKGROUND DATA: The efficacy of the Biodesign Surgisis anal fistula plug in healing anal fistulae is uncertain. METHODS: Participants were randomized to the fistula plug with surgeon's preference (advancement flap, cutting seton, fistulotomy, Ligation of the Intersphincteric Fistula Tract procedure). The primary outcome was faecal incontinence quality of life (FIQoL) at 12-months. Secondary outcomes were fistula healing, incontinence rates, and complication and reintervention rates. RESULTS: Between May 2011 and March 2016, 304 participants were randomized to fistula plug or surgeon's preference. No differences were seen in FIQoL between the 2 groups at 12 months. Clinical fistula healing was reported in 66/122 (54%) of the fistula plug and 66/119 (55%) of the surgeon's preference groups at 12 months. Fecal incontinence rates improved marginally in both the groups. Complications and reinterventions were frequent, with significantly more complications in the fistula plug group at 6-weeks (49/142, 35% vs 25/137, 18%; P=0.002). The mean total costs were £2738 (s.d. £1151) for the fistula plug and £2308 (s.d. £1228) for the surgeon's preference group (mean difference +£430, P=0.0174). The average total quality adjusted life years (QALYs) gained was marginally higher in the fistula plug group. The fistula plug was 35% to 45% likely to be cost-effective across a willingness to pay threshold of £20,000 to £30,000 / QALY. CONCLUSIONS: The Biodesign Surgisis anal fistula plug is associated with similar FIQoL and healing rates to surgeon's preference at 12 months. Higher costs and highly uncertain gains in QALYs mean that the fistula plug may not be considered as a cost-effective treatment in the UK NHS.

Effect of dual task activity on reaction time in males and females.

The present study was designed to compare the auditory and visual reaction time on an Audiovisual Reaction Time Machine with the concomitant use of mobile phones in 52 women and 30 men in the age group of 18-40 years. Males showed significantly (p < 0.05) shorter reaction times, both auditory and visual, than females both during single task and multi task performance. But the percentage increase from their respective baseline auditory reaction times, was more in men than women during multitasking, in hand held (24.38% & 18.70% respectively) and hands free modes (36.40% & 18.40% respectively) of the use of cell phone. VRT increased non significantly during multitasking in both the groups. However, the multitasking per se has detrimental effect on the reaction times in both the groups studied. Hence, it should best be avoided in crucial and high attention demanding tasks like driving.

A Study to Assess Biochemical Profile of Tobacco Chewers with Chewing Habit Over a Period of 10 Years.

The study was conducted to evaluate the systemic adverse effects of smokeless tobacco (SLT) on hematological as well as other biochemical parameters and find out if any correlation between them which may be worthy of creating awareness among the masses against its usage. The current observational study was carried out among 250 tobacco chewers, and complete hemogram, LFT profile, and electrolyte profile were studied. The mean values of hemoglobin (Hb) gram % was 12.74 ± 1.6, total leucocyte count (TLC/cu mm) is 6608.33 ± 1752.083, and platelet count lakh cell/cu mm is 2.55 ±0.806. The mean values of Na+ mmol/1 of the S. electrolyte profile was 132 ± 18.05 and K+ mmol/1 was 3.89 ± 0.538. The study deliberates imperative perception into smokeless tobacco-mediated effects on body systemic functions and reports a crucial part into SLT-mediated effects on biochemical profile and metabolism which can be revealed in promoting tobacco cessation.

Hand hygiene compliance of respiratory physiotherapists: An analysis of trends over eight years including the COVID-19 pandemic period.

BACKGROUND: Respiratory physiotherapists (RPs) are an integral part of healthcare workers delivering care to intubated patients. Our study aimed to evaluate the effect of awareness campaigns on hand hygiene (HH) compliance among RPs. METHOD: An observational single-center study was conducted between 2015 and 2022 in different ICU types in both adult and paediatric settings. The hand hygiene compliance rates were monitored prospectively and the quality improvement interventions included various hand hygiene campaigns and awareness sessions with RPs. Compliance was calculated as a percentage of events over total opportunities observed. RESULTS: There was a significant increase in compliance rates for all five moments of HH (p-value: <0.05). Overall, mean compliance rate in ICUs was significantly higher than wards for Moment 1 (p-value: 0.0045), Moment 4 (p-value: 0.0372) and Moment 5 (p-value: 0.0036) by 24.2%, 22.7% and 21.5% respectively. Also, paediatric ICUs had higher HH compliance than adult ICUs for Moment 1 (87.5% vs 61.1%; p-value: 0.0459) and Moment 4 (93.7% vs 79.3%; p-value: 0.0255). A significant increase in HH compliance was observed in post-COVID-19 period compared to pre-COVID-19 period with respect to Moment 1, 2 and 5. CONCLUSION: This study adds to the almost non-existent literature on this important category of healthcare workers working in respiratory ICUs. Our results project an increase compliance after the HH awareness programmes over the years among RP which is critical to prevent spread infection by multidrug resistant organisms among the hospitals.

Bitter melon juice activates cellular energy sensor AMP-activated protein kinase causing apoptotic death of human pancreatic carcinoma cells.

Prognosis of pancreatic cancer is extremely poor, suggesting critical needs for additional drugs to improve disease outcome. In this study, we examined efficacy and associated mechanism of a novel agent bitter melon juice (BMJ) against pancreatic carcinoma cells both in culture and nude mice. BMJ anticancer efficacy was analyzed in human pancreatic carcinoma BxPC-3, MiaPaCa-2, AsPC-1 and Capan-2 cells by 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide, cell death enzyme-linked immunosorbent assay and annexin/propidium iodide assays. BMJ effect on apoptosis regulators was assessed by immunoblotting. In vivo BMJ efficacy was evaluated against MiaPaCa-2 tumors in nude mice, and xenograft was analyzed for biomarkers by immunohistochemistry (IHC). Results showed that BMJ (2-5% v/v) decreases cell viability in all four pancreatic carcinoma cell lines by inducing strong apoptotic death. At molecular level, BMJ caused caspases activation, altered expression of Bcl-2 family members and cytochrome-c release into the cytosol. Additionally, BMJ decreased survivin and X-linked inhibitor of apoptosis protein but increased p21, CHOP and phosphorylated mitogen-activated protein kinases (extracellular signal-regulated kinase 1/2 and p38) levels. Importantly, BMJ activated adenosine monophosphate-activated protein kinase (AMPK), a biomarker for cellular energy status, and an AMPK inhibitor (Compound C) reversed BMJ-induced caspase-3 activation suggesting activated AMPK involvement in BMJ-induced apoptosis. In vivo, oral administration of lyophilized BMJ (5mg in 100 µl water/day/mouse) for 6 weeks inhibited MiaPaCa-2 tumor xenograft growth by 60% (P < 0.01) without noticeable toxicity in nude mice. IHC analyses of MiaPaCa-2 xenografts showed that BMJ also inhibits proliferation, induces apoptosis and activates AMPK in vivo. Overall, BMJ exerts strong anticancer efficacy against human pancreatic carcinoma cells, both in vitro and in vivo, suggesting its clinical usefulness.

Differential effect of grape seed extract against human non-small-cell lung cancer cells: the role of reactive oxygen species and apoptosis induction.

The present study examines grape seed extract (GSE) efficacy against a series of non-small-cell lung cancer (NSCLC) cell lines that differ in their Kras and p53 status to establish GSE potential as a cytotoxic agent against a wide range of lung cancer cells. GSE suppressed growth and induced apoptotic death in NSCLC cells irrespective of their k-Ras status, with more sensitivity toward H460 and H322 (wt k-Ras) than A549 and H1299 cells (mutated k-Ras). Mechanistic studies in A549 and H460 cells, selected, based on comparative efficacy of GSE at higher and lower doses, respectively, showed that apoptotic death involves cytochrome c release associated caspases 9 and 3 activation, and poly (ADP-ribosyl) polymerase cleavage, strong phosphorylation of ERK1/2 and JNK1/2, downregulation of cell survival proteins, and upregulated proapoptotic Bak expression. Importantly, GSE treatment caused a strong superoxide radical-associated oxidative stress, significantly decreased intracellular reduced glutathione levels, suggesting, for the first time, the involvement of GSE-caused oxidative stress in its apoptotic inducing activity in these cells. Because GSE is a widely-consumed dietary agent with no known untoward effects, our results support future studies to establish GSE efficacy and usefulness against NSCLC control.

Quantification of diurnal variation in "glove hygiene" compliance in COVID ICUs: An exploratory study.

BACKGROUND: Hand hygiene compliance (HHC) monitoring is almost always done in daytime. Documentation of HHC in health care workers (HCWs) is limited during odd hours and nighttime. The objective of the study was to determine diurnal variation in HHC in different categories of health care workers in tertiary care hospital in North India. METHODS: A prospective, observational study was conducted in 3 COVID-19 intensive care units (ICUs) with closed-circuit television (CCTV) cameras. Dedicated infection control nurses monitored HHC among various HCWs (doctors, nursing staff, technicians, hospital and sanitary attendants) during day and nighttime, in 20-minute durations. The difference in HHC by-professional category and for each WHO moment was assessed using χ² test and P value. RESULTS: A total of 705 opportunities were observed over a period of 7 days, with overall compliance of 53%. Day and nighttime compliance was recorded to be 60.7% and 42.1%, respectively (P < .001). HCC was highest amongst resident doctors with little diurnal variation. However, nurses and housekeeping staff exhibited significant diurnal variation. The compliance at "after" moments was much higher than "before" moments in all professional categories. CONCLUSION: There was a significant decrease in compliance during nighttime, amongst all HCWs, with maximum variation exhibited by nursing staff. The present study underlines the importance of monitoring HHC at odd hours, to elicit a more accurate picture round the clock. Health care facilities monitoring compliance only during the daytime may substantially overestimate HHC.

Plasma Fibrinogen Degradation Products as the Nonsurgical Diagnostic Tool for Oral Submucous Fibrosis: A Systematic Review.

Aims and Objectives: Oral submucous fibrosis (OSMF) is known to be one of the most common premalignant conditions of the oral cavity. Areca nut (AN) is considered to be the disease's primary cause, while there are other potential causes as well. However, routine clinical practice has revealed that not all people who chew AN exhibit clinical signs of OSMF, and few people are reported to have it even without chewing AN. So, there must be other factors contributing to OSMF. Plasma fibrinogen degradation products (FDPs) have recently been discovered to be an early sign of this disease, indicating a potential link between the two. This review aims to examine the studies which have been published in the literature that explain the role of plasma FDPs in contributing to OSMF. Materials and Methods: An electronic search of the published literature was performed without publication year limitation in PubMed/ Medline, Scopus, Google Scholar, Web of Science, Science Direct, Embase, and Research gate databases, using mesh keywords like ('Oral submucous fibrosis' OR 'Oral submucous fibrosis') AND ('Fibrinogen degradation products' OR 'Plasma fibrinogen degradation products') AND ('Clinical grades' OR 'Histological grades') AND ('Diagnosis'). A manual search of all related journals was also done. We also referred to the reference lists of papers. The risk of bias was evaluated with the GRADE criteria (from the Grading of Recommendations Assessment, Development, and Evaluation Working Group). Results: The search revealed a total of 12 relevant studies from 1979 to 2022. Nine out of 12 studies demonstrated the definite presence of plasma FDPs in such cases. Conclusions: Although the studies documented in the literature showing evidence of plasma FDPs in patients with OSMF are very few in number, their detection signifies an important clinical finding. More research is still required in this aspect to establish stronger evidence.

Lung cancer metastasizing to salivary glands: Systematic review.

ABSTRACTS: Metastasis to salivary glands from the secondary source outside the head and neck region is extremely rare and Carcinoma Lung is one of the rarest sources of distant spread to salivary glands. Owing to missed diagnosis and misdiagnosis, accurate identification of clinical and pathological aspects of these metastatic lesions remains a challenging task. Many studies regarding metastasis to the oral cavity have been already documented in the literature, but very little research work has been done to analyse the cases of lung cancer metastasis as the sole primary source, particularly to salivary glands. Thus this review was conducted to analyse the published cases of lung cancer metastasizing to salivary glands as the only primary source till date. An electronic search of the published literature was performed without publication year limitation in PubMed/ Medline, Scopus, Google Scholar, Web of Science, Science direct, Embase, and Research gate databases, using Mesh keywords like (Lung cancer', OR 'Lung carcinoma), AND (Metastasis OR Metastases), And (Salivary glands OR Parotid gland OR Submandibular gland OR Sublingual gland). We also searched all related journals manually. The reference list of all articles was also checked. Our research revealed 34 relevant papers between 1965-2022 with a total of 44 patients. The most prevalent diagnosed metastatic Lung cancer was Small cell lung cancer. Parotid was the most common gland involved in metastasis. 48% of patients died of metastasis with a mean survival time of 2.2 years. Salivary gland metastasis from Lung cancer is very rare and has a poor prognosis. More cases need to be published in order to raise awareness of these lesions and gain a better understanding of their characteristics.

Hand hygiene behavior change: a review and pilot study of an automated hand hygiene reminder system implementation in a public hospital.

Objective: To review and study implementation of an automated hand hygiene reminder system (AHHRS). Design: Prospective, nonrandomized, before-after quality improvement pilot study conducted over 6 months. Setting: Medical-surgical unit (MSU) and medical intensive care unit (MICU) at a public hospital in New York City. Participants: There were 2,642 healthcare worker observations in the direct observation (DO) period versus 265,505 in the AHHRS period, excluding AHHRS observations collected during the 1-month crossover period when simultaneous DO occurred. Intervention: We compared hand hygiene adherence (HHA) measured by DO prior to the pilot and after AHHRS implementation. We compared changes in HHA and potential cross-contamination events (CCEs) (room exit and subsequent entry without HHA) from baseline for each biweekly period during the pilot. Results: Engagement, education/training, data transparency, and optimization period resulted in successful implementation and adoption of the AHHRS. Observations were greater utilizing AHHRS than DO (265,505 vs 2,642, P < .01). Due to the expected Hawthorne effect, HHA was significantly less for AHHRS than DO in MSU (90.99% vs 97.21%, P < .01) and MICU (91.21% vs 98.65%, P < .01). HHA significantly improved from 86.47% to 89.68% in MSU (P < .001) and 85.93% to 91.24% in the MICU (P < .001) from the first biweekly period of AHHRS utilization to the last. CCE decreased from 73.42% to 65.11% in the MSU and significantly decreased from 81.22% to 53.19% in the MICU (P < .05). Conclusions: We describe how an AHHRS approach was successfully implemented at our facility. With ongoing feedback and system optimization, AHHRS improved HHA and reduced CCE over time.

Generation of reactive oxygen species by grape seed extract causes irreparable DNA damage leading to G2/M arrest and apoptosis selectively in head and neck squamous cell carcinoma cells.

Head and neck squamous cell carcinoma (HNSCC) accounts for 6% of all malignancies in USA and unfortunately the recurrence of secondary primary tumors and resistance against conventional treatments decrease the overall 5 year survival rate in HNSCC patients. Thus, additional approaches are needed to control HNSCC. Here, for the first time, employing human HNSCC Detroit 562 and FaDu cells as well as normal human epidermal keratinocytes, we investigate grape seed extract (GSE) efficacy and associated mechanism in both cell culture and nude mice xenografts. GSE selectively inhibited the growth and caused cell cycle arrest and apoptotic death in both Detroit 562 and FaDu cells by activating DNA damage checkpoint cascade, including ataxia telangiectasia mutated/ataxia telangiectasia-Rad3-related-checkpoint kinase 1/2-cell division cycle 25C as well as caspases 8, 9 and 3. Consistent with these results, GSE treatment resulted in a strong DNA damage and a decrease in the levels of DNA repair molecules breast cancer gene 1 and Rad51 and DNA repair foci. GSE-caused accumulation of intracellular reactive oxygen species was identified as a major mechanism of its effect for growth inhibition, DNA damage and apoptosis, which was remarkably reversed by antioxidant N-acetylcysteine. GSE feeding to nude mice decreased Detroit 562 and FaDu xenograft tumor growth by 67 and 65% (P < 0.001), respectively. In immunohistochemical analysis, xenografts from GSE-fed groups showed decreased proliferation but increased DNA damage and apoptosis. Together, these findings show that GSE targets both DNA damage and repair and provide mechanistic insights for its efficacy selectively against HNSCC both in cell culture and mouse xenograft, supporting its translational potential against HNSCC.

Empowered Nurses: A Win-Win Situation in Pediatric Critical Care.

The atmosphere of a pediatric intensive care unit (PICU) is charged, fast paced, stressful, and tiring with emphasis on precision of care. Pediatric critical care nursing is still in its infancy stage in India and other low middle income countries. The lack of resources, staff shortage, migration and brain drain are persistent issues in India. There is lack of career advancement as well as exposure to research activities. Keeping these barriers in mind, over the years, we have adopted certain multipronged strategies in our PICU with the objective of empowering, and motivating our nursing personnel. We have been able to 'build a horizontal team' where each member feels wanted and works to his/her maximum capacity. This model of nurse empowerment may be reproduced by other institutions especially in low middle income countries that are also struggling with similar problems.

Quality-of-life outcomes in older patients with early-stage rectal cancer receiving organ-preserving treatment with hypofractionated short-course radiotherapy followed by transanal endoscopic microsurgery (TREC): non-randomised registry of patients unsuitable for total mesorectal excision.

BACKGROUND: Older patients with early-stage rectal cancer are under-represented in clinical trials and, therefore, little high-quality data are available to guide treatment in this patient population. The TREC trial was a randomised, open-label feasibility study conducted at 21 centres across the UK that compared organ preservation through short-course radiotherapy (SCRT; 25 Gy in five fractions) plus transanal endoscopic microsurgery (TEM) with standard total mesorectal excision in adults with stage T1-2 rectal adenocarcinoma (maximum diameter ≤30 mm) and no lymph node involvement or metastasis. TREC incorporated a non-randomised registry offering organ preservation to patients who were considered unsuitable for total mesorectal excision by the local colorectal cancer multidisciplinary team. Organ preservation was achieved in 56 (92%) of 61 non-randomised registry patients with local recurrence-free survival of 91% (95% CI 84-99) at 3 years. Here, we report acute and long-term patient-reported outcomes from this non-randomised registry group. METHODS: Patients considered by the local colorectal cancer multidisciplinary team to be at high risk of complications from total mesorectal excision on the basis of frailty, comorbidities, and older age were included in a non-randomised registry to receive organ-preserving treatment. These patients were invited to complete questionnaires on patient-reported outcomes (the European Organisation for Research and Treatment of Cancer Quality of Life [EORTC-QLQ] questionnaire core module [QLQ-C30] and colorectal cancer module [QLQ-CR29], the Colorectal Functional Outcome [COREFO] questionnaire, and EuroQol-5 Dimensions-3 Level [EQ-5D-3L]) at baseline and at months 3, 6, 12, 24, and 36 postoperatively. To aid interpretation, data from patients in the non-randomised registry were compared with data from those patients in the TREC trial who had been randomly assigned to organ-preserving therapy, and an additional reference cohort of aged-matched controls from the UK general population. This study is registered with the ISRCTN registry, ISRCTN14422743, and is closed. FINDINGS: Between July 21, 2011, and July 15, 2015, 88 patients were enrolled onto the TREC study to undergo organ preservation, of whom 27 (31%) were randomly allocated to organ-preserving therapy and 61 (69%) were added to the non-randomised registry for organ-preserving therapy. Non-randomised patients were older than randomised patients (median age 74 years [IQR 67-80] vs 65 years [61-71]). Organ-preserving treatment was well tolerated among patients in the non-randomised registry, with mild worsening of fatigue; quality of life; physical, social, and role functioning; and bowel function 3 months postoperatively compared with baseline values. By 6-12 months, most scores had returned to baseline values, and were indistinguishable from data from the reference cohort. Only mild symptoms of faecal incontinence and urgency, equivalent to less than one episode per week, persisted at 36 months among patients in both groups. INTERPRETATION: The SCRT and TEM organ-preservation approach was well tolerated in older and frailer patients, showed good rates of organ preservation, and was associated with low rates of acute and long-term toxicity, with minimal effects on quality of life and functional status. Our findings support the adoption of this approach for patients considered to be at high risk from radical surgery. FUNDING: Cancer Research UK.

Grape seed extract upregulates p21 (Cip1) through redox-mediated activation of ERK1/2 and posttranscriptional regulation leading to cell cycle arrest in colon carcinoma HT29 cells.

Abnormalities in cell cycle progression provide unlimited replicative potential to cancer cells, and therefore targeting of key cell cycle regulators could be a sound cancer chemopreventive strategy. Earlier, we found that grape seed extract (GSE) increases Cip/p21 protein level and inhibits growth and induces apoptosis in human colon carcinoma HT29 cells both in vitro and in vivo. However, the mechanism of GSE-induced p21 upregulation and its role in biological efficacy of GSE are not known, which were investigated here. GSE treatment of HT29 cells resulted in a strong dose- and time-dependent phosphorylation of extracellular signal regulated kinase 1/2 (ERK1/2), consistent with p21 induction. The inhibition of sustained ERK1/2 activation by GSE using pharmacological inhibitors abrogated GSE-induced p21 upregulation. Furthermore, pretreatment of cells with N-acetylcysteine inhibited GSE-induced ERK1/2 phosphorylation as well as p21 upregulation, suggesting the involvement of GSE-induced oxidative stress as an upstream event. Consistent with this, GSE also decreased intracellular level of reduced glutathione. Next, we determined whether GSE-induced signaling regulates p21 expression at transcriptional and/or translational levels. GSE was found to increase the stability of p21 message with resultant increase in p21 protein level, but it did not alter the protein stability to a great extent. Importantly, knock-down of p21 abrogated GSE-induced G(1) arrest suggesting that p21 induction by GSE is essential for its G(1) arrest effect. Together, our results for the first time identify a central role of p21 induction and associated mechanism in GSE-induced cell cycle arrest in HT29 cells.

Radical surgery versus organ preservation via short-course radiotherapy followed by transanal endoscopic microsurgery for early-stage rectal cancer (TREC): a randomised, open-label feasibility study.

BACKGROUND: Radical surgery via total mesorectal excision might not be the optimal first-line treatment for early-stage rectal cancer. An organ-preserving strategy with selective total mesorectal excision could reduce the adverse effects of treatment without substantially compromising oncological outcomes. We investigated the feasibility of recruiting patients to a randomised trial comparing an organ-preserving strategy with total mesorectal excision. METHODS: TREC was a randomised, open-label feasibility study done at 21 tertiary referral centres in the UK. Eligible participants were aged 18 years or older with rectal adenocarcinoma, staged T2 or lower, with a maximum diameter of 30 mm or less; patients with lymph node involvement or metastases were excluded. Patients were randomly allocated (1:1) by use of a computer-based randomisation service to undergo organ preservation with short-course radiotherapy followed by transanal endoscopic microsurgery after 8-10 weeks, or total mesorectal excision. Where the transanal endoscopic microsurgery specimen showed histopathological features associated with an increased risk of local recurrence, patients were considered for planned early conversion to total mesorectal excision. A non-randomised prospective registry captured patients for whom randomisation was considered inappropriate, because of a strong clinical indication for one treatment group. The primary endpoint was cumulative randomisation at 12, 18, and 24 months. Secondary outcomes evaluated safety, efficacy, and health-related quality of life assessed with the European Organisation for Research and Treatment of Cancer (EORTC) QLQ C30 and CR29 in the intention-to-treat population. This trial is registered with the ISRCTN Registry, ISRCTN14422743. FINDINGS: Between Feb 22, 2012, and Dec 19, 2014, 55 patients were randomly assigned at 15 sites; 27 to organ preservation and 28 to radical surgery. Cumulatively, 18 patients had been randomly assigned at 12 months, 31 at 18 months, and 39 at 24 months. No patients died within 30 days of initial treatment, but one patient randomly assigned to organ preservation died within 6 months following conversion to total mesorectal excision with anastomotic leakage. Eight (30%) of 27 patients randomly assigned to organ preservation were converted to total mesorectal excision. Serious adverse events were reported in four (15%) of 27 patients randomly assigned to organ preservation versus 11 (39%) of 28 randomly assigned to total mesorectal excision (p=0·04, χ2 test). Serious adverse events associated with organ preservation were most commonly due to rectal bleeding or pain following transanal endoscopic microsurgery (reported in three cases). Radical total mesorectal excision was associated with medical and surgical complications including anastomotic leakage (two patients), kidney injury (two patients), cardiac arrest (one patient), and pneumonia (two patients). Histopathological features that would be considered to be associated with increased risk of tumour recurrence if observed after transanal endoscopic microsurgery alone were present in 16 (59%) of 27 patients randomly assigned to organ preservation, versus 24 (86%) of 28 randomly assigned to total mesorectal excision (p=0·03, χ2 test). Eight (30%) of 27 patients assigned to organ preservation achieved a complete response to radiotherapy. Patients who were randomly assigned to organ preservation showed improvements in patient-reported bowel toxicities and quality of life and function scores in multiple items compared to those who were randomly assigned to total mesorectal excision, which were sustained over 36 months' follow-up. The non-randomised registry comprised 61 patients who underwent organ preservation and seven who underwent radical surgery. Non-randomised patients who underwent organ preservation were older than randomised patients and more likely to have life-limiting comorbidities. Serious adverse events occurred in ten (16%) of 61 non-randomised patients who underwent organ preservation versus one (14%) of seven who underwent total mesorectal excision. 24 (39%) of 61 non-randomised patients who underwent organ preservation had high-risk histopathological features, while 25 (41%) of 61 achieved a complete response. Overall, organ preservation was achieved in 19 (70%) of 27 randomised patients and 56 (92%) of 61 non-randomised patients. INTERPRETATION: Short-course radiotherapy followed by transanal endoscopic microsurgery achieves high levels of organ preservation, with relatively low morbidity and indications of improved quality of life. These data support the use of organ preservation for patients considered unsuitable for primary total mesorectal excision due to the short-term risks associated with this surgery, and support further evaluation of short-course radiotherapy to achieve organ preservation in patients considered fit for total mesorectal excision. Larger randomised studies, such as the ongoing STAR-TREC study, are needed to more precisely determine oncological outcomes following different organ preservation treatment schedules. FUNDING: Cancer Research UK.

Silibinin exerts sustained growth suppressive effect against human colon carcinoma SW480 xenograft by targeting multiple signaling molecules.

PURPOSE: Earlier, we reported the strong preventive efficacy of silibinin against colorectal cancer (CRC), but its usefulness against established CRC or effect of its withdrawal on CRC growth remained unknown. Present study focused on these important issues by employing two different treatment protocols in advanced human CRC SW480 xenograft in nude mice. METHODS: In the first treatment protocol, silibinin was fed for 28 days (200 mg/kg body weight, 5 days/week) to mice with growing SW480 xenograft; thereafter, tumor growth was monitored for additional 3 weeks without silibinin treatment. In the second protocol, silibinin treatment was started after 25 days of SW480 cells injection (established tumors), and tumor growth was studied 4 days, 8 days and 16 days after silibinin treatment. RESULTS: In both treatment protocols, silibinin had strong and sustained inhibitory effect on xenograft growth. Detailed xenograft analyses showed that silibinin, in both treatment protocols, exerts anti-proliferative, pro-apoptotic and anti-angiogenic effects. Further, silibinin reduced the expression of ß-catenin and phospho-GSK3ß in xenograft tissues. Silibinin also targeted signaling molecules involved in CRC proliferation and survival (cyclin D1, c-Myc and survivin) as well as angiogenesis regulators (VEGF and iNOS). CONCLUSIONS: Collectively, these findings substantiate silibinin's therapeutic efficacy against CRC, advocating its translational potential.

Influence of gallate esterification on the activity of procyanidin B2 in androgen-dependent human prostate carcinoma LNCaP cells.

PURPOSE: Present study assessed the influence of gallate esterification on the anti-cancer activity of procyanidin B2 (B2) in androgen-dependent human prostate carcinoma LNCaP cells employing B2-3,3'-di-O-gallate (B2-G(2)), two mono-gallate esters B2-3-O-gallate (B2-3G) and B2-3'-O-gallate (B2-3'G) and the parent compound B2, all isolated from grape seed extract (GSE). MATERIALS AND METHODS: Study compounds were isolated from GSE by several chromatographic steps and structures determined by a combination of enzymatic hydrolysis, mass spectrometry and comparisons with standards. Cells, treated with these compounds, were assessed for viability and apoptosis and examined by western blotting. RESULTS: Gallate esters B2-G(2), B2-3G and B2-3'G significantly decreased LNCaP cell viability; however, B2 and gallic acid were ineffective. Furthermore, only B2-G(2) also significantly decreased cell growth. Decreases in cell viability were largely due to apoptosis induction with B2-G(2) and B2-3'G exhibiting comparable effects, whereas B2-3G was less effective. In mechanistic studies, B2-G(2) and B2-3'G treatments caused caspases-9 and -3 and PARP cleavage, and down-regulated Bcl-2, Bcl-Xl and androgen receptor levels. CONCLUSION: Together, our findings demonstrate anti-PCA efficacy of B2-G(2) and suggest that a gallate ester moiety at 3' position of procyanidin B2 contributes more extensively toward the biological activity of the di-gallate ester than esterification of position 3.