Long-Term Outcomes in Early versus Limited Response to Anti-VEGF Treatment for Retinal Vein Occlusion.

OBJECTIVE: Macular edema secondary to retinal vein occlusion (RVO) is a sight-threatening condition. Previous studies showed that early responders (ERs) who respond well to anti-VEGF injections within 3 months of treatment have better outcomes, as measured by best visual acuity (BVA) and central subfield thickness (CST) at 12 months postinjection initiation compared with limited early responders (LERs). This study analyzed whether ER eyes continue to respond better than LER eyes over longer periods. This study also aimed to identify baseline comorbidities associated with response status. DESIGN: Retrospective cohort study. PARTICIPANTS: Patients aged > 18 years with RVO-related macular edema treated with anti-VEGF injections. METHODS: Patients were categorized as ERs or LERs. Limited early responder eyes were defined as having CST reduction < 10%, BVA gain < 5 ETDRS letters, or both at 3 months after anti-VEGF initiation. Best visual acuity and CST changes over the 24- and 36-month period after the first anti-VEGF treatment were compared between ERs and LERs. Patient characteristics and systemic comorbidities were identified by chart review. Statistical analysis involved the Levene test, Welch t test, and Welch analysis of variance. MAIN OUTCOME MEASURES: Best visual acuity and CST changes over the initial 24-month and 36-month periods after treatment. RESULTS: The 24-month cohort included 68 ERs and 39 LERs, and the 36-month cohort included 58 ERs and 33 LERs. At the 24-month time point, there were significant differences in BVA and CST gains between ERs (+19.8 letters, -221.2 um) and LERs (-2.4 letters, -90.1 um; P < 0.001, P < 0.01). Similarly, at 36 months, there were significant differences in BVA and CST gains between ERs (+17.7 letters, -229.3 um) and LERs (+1.3 letters, -128 um; P < 0.001, P < 0.05). After controlling for differences in baseline BVA and CST, only the 24-month change in BVA remained significant (P < 0.001). There were no significant associations between response status and cardiopulmonary, endocrine, and oncologic comorbidities. CONCLUSIONS: Early responder eyes with branched retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO) have better functional responses to anti-VEGF injections at 24 months compared with LER eyes, even after controlling for baseline differences. Early identification of eyes as ERs or LERs in BRVO and CRVO may predict long-term functional prognoses. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

An Observational Study on the Utility of Lab Parameters in Evaluating the Severity of Patients in South India with Covid-19.

Laboratory testing has been extremely helpful in determining the severity and determining the course of treatment for COVID-19 patients. Our aim has been to look for variables of patient's clinical and laboratory profile for two weeks and to observe their significance. Observational, Cross-sectional study. Data from the clinic and laboratory were compiled on Google form after informed consent from the patient. Statistical analysis was done using the Mann-Whitney U and unpaired t test. Population statistics included 202 patients (1st week) and 161 patients (2nd week), with the mean age of 61 ± 18 years. Most patients fell under the mild category (SPO2 >94%). High body mass index (n = 119) and hypertensive (n = 98) were the most common comorbidities observed. Diabetes, cardiovascular and respiratory diseases are the other comorbidities studied in this study. Hypoalbuminemia (n = 194) is the most deranged laboratory parameter in mild category, followed by lymphopenia (n = 109). In severe category also, hypoalbuminemia (n = 13) was deranged more. Other laboratory parameters included are CRP, D-Dimer, neutrophil and lymphocyte count. This study showed that albumin is a good predictor for estimating the severity of COVID-19 patients especially in the first week of their admission.

Intranasally administered extracellular vesicles from human induced pluripotent stem cell-derived neural stem cells quickly incorporate into neurons and microglia in 5xFAD mice.

Introduction: Extracellular vesicles (EVs) released by human-induced pluripotent stem cell (hiPSC)-derived neural stem cells (NSCs) have robust antiinflammatory and neurogenic properties due to therapeutic miRNAs and proteins in their cargo. Hence, hiPSC-NSC-EVs are potentially an excellent biologic for treating neurodegenerative disorders, including Alzheimer's disease (AD). Methods: This study investigated whether intranasally (IN) administered hiPSC-NSC-EVs would quickly target various neural cell types in the forebrain, midbrain, and hindbrain regions of 3-month-old 5xFAD mice, a model of ß-amyloidosis and familial AD. We administered a single dose of 25 × 109 hiPSC-NSC-EVs labeled with PKH26, and different cohorts of naïve and 5xFAD mice receiving EVs were euthanized at 45 min or 6 h post-administration. Results: At 45 min post-administration, EVs were found in virtually all subregions of the forebrain, midbrain, and hindbrain of naïve and 5xFAD mice, with predominant targeting and internalization into neurons, interneurons, and microglia, including plaque-associated microglia in 5xFAD mice. EVs also came in contact with the plasma membranes of astrocytic processes and the soma of oligodendrocytes in white matter regions. Evaluation of CD63/CD81 expression with the neuronal marker confirmed that PKH26 + particles found within neurons were IN administered hiPSC-NSC-EVs. At 6 h post-administration, EVs persisted in all cell types in both groups, with the distribution mostly matching what was observed at 45 min post-administration. Area fraction (AF) analysis revealed that, in both naïve and 5xFAD mice, higher fractions of EVs incorporate into forebrain regions at both time points. However, at 45 min post-IN administration, AFs of EVs within cell layers in forebrain regions and within microglia in midbrain and hindbrain regions were lower in 5xFAD mice than naïve mice, implying that amyloidosis reduces EV penetrance. Discussion: Collectively, the results provide novel evidence that IN administration of therapeutic hiPSC-NSC-EVs is an efficient avenue for directing such EVs into neurons and glia in all brain regions in the early stage of amyloidosis. As pathological changes in AD are observed in multiple brain areas, the ability to deliver therapeutic EVs into various neural cells in virtually every brain region in the early stage of amyloidosis is attractive for promoting neuroprotective and antiinflammatory effects.

Designing face resemblance technique using near set theory under varying facial features.

Near sets (also called Descriptively Near Sets) classify nonempty sets of objects based on object feature values. The Near Set Theory provides a framework for measuring the similarity of objects based on features that describe them in much the same way humans perceive the similarity of objects. This paper presents a novel approach for face recognition using Near Set Theory that takes into account variations in facial features due to varying facial expressions, and facial plastic surgery. In the proposed work, we demonstrate two-fold usage of Near set theory; firstly, Near Set Theory as a feature selector to select the plastic surgery facial features with the help of tolerance classes, and secondly, Near Set Theory as a recognizer that uses selected prominent intrinsic facial features which are automatically extracted through the deep learning model. Extensive experimentation was performed on various facial datasets such as YALE, PSD, and ASPS. Experimentation demonstrates 93% of accuracy on the YALE face dataset, 98% of accuracy on the PSD dataset, and 98% of accuracy on the ASPS dataset. A detailed comparative analysis of the proposed work of facial resemblance with other state-of-the-art algorithms is presented in this paper. The experimentation results effectively classify face resemblance using Near Set Theory, which has outperformed several state-of-the-art classification approaches.

A systemic review and meta-analysis of Aflibercept plus FOLFIRI regimen as a second-line treatment for metastatic colorectal cancer: A PRISMA compliant pooled analysis of randomized controlled trials and single arm studies to assess efficacy and safety.

BACKGROUND AND OBJECTIVE: Aflibercept; a decoy receptor for vascular endothelial growth factors (VEGFs) and placental growth factor (PLGF), in combination with FOLFIRI (leucovorin calcium, fluorouracil, irinotecan hydrochloride) chemotherapy regime, was FDA approved in 2012 as second-line salvage chemotherapy for metastatic colorectal cancer (mCRC). This is the first systematic review, and meta-analysis-based evidence to determine the efficacy and safety of Aflibercept plus FOLFIRI regimen pooling randomized controlled trials and single-arm studies. METHOD: PubMed, Cochrane library, Embase, and Clinical trial.gov were systematically searched for published randomized controlled trials, single-arm studies, and national patient programs on aflibercept plus FOLFIRI chemotherapy for the treatment of mCRC till 11/10/2022. RESULT: Ten studies met the inclusion criteria comprising 1075 patients for efficacy studies and 2027 patients for safety studies. The pooled prevalences were 18% (95% CI, 5%-37%, p = 0.00) for 12 m PFS and 61% (95% CI, 53-68%, p = 0.00) for 12 m OS. The pooled prevalences were 69% (95% CI, 55-82%, p = 0.00) for any grade 3-4 toxicities, 10% (95% CI, 5-16%, p = 0.00) for grade 3-4 diarrhea, 13% (95% CI, 5-24%, p = 0.00) for grade 3-4 hypertension, 31% (95% CI, 22-40%, p = 0.00) for grade 3-4 neutropenia and 5% (95% CI, 2-7%, p = 0.00) for grade 3-4 venous thromboembolic event. CONCLUSION: Our meta-analysis shows that the aflibercept plus FOLFIRI combination shows better survival efficacies however; it is also associated with more high-grade adverse events.

Characterizing and Predicting Limited Early Response in Eyes With Retinal Vein Occlusion Using Machine Learning in Routine Clinical Practice.

OBJECTIVE: To characterize and predict limited early responders (LER) in eyes with retinal vein occlusion (RVO) treated with anti-vascular endothelial growth factor (anti-VEGF). PATIENTS AND METHODS: This retrospective cohort study of 116 eyes with edema secondary to RVO characterized early responders (ER) and LER 3 months after initiating anti-VEGF treatment. Baseline characteristics and 12-month outcomes were compared. A machine learning (ML) algorithm was developed to predict LER. RESULTS: At baseline, LER had higher best-corrected visual acuity (BCVA) than ER (P< 0.0001) and lower central subfield thickness (CST) than ER (P< 0.01). At 12 months, change in BCVA was + 0.8 and + 21.4 letters, and change in CST was -104.4 and -187.1 µm for LER and ER, respectively (P < 0.0001, P < 0.05). The ML algorithm achieved area under the receiver operating characteristic curve = 0.73. CONCLUSION: ER eyes experienced greater functional and anatomical improvements at 12 months in routine clinical practice than LER. The ML algorithm achieved moderately high performance predicting LER. [Ophthalmic Surg Lasers Imaging Retina 2023;54:231-237.].

Current investigative modalities for detecting and staging lung cancers: a comprehensive summary.

This narrative review compares the advantages and drawbacks of imaging and other investigation modalities which currently assist with lung cancer diagnosis and staging, as well as those which are not routinely indicated for this. We examine plain film radiography, computed tomography (CT) (alone, as well as in conjunction with positron emission tomography (PET)), magnetic resonance imaging (MRI), ultrasound, and newer techniques such as image-guided bronchoscopy (IGB) and robotic bronchoscopy (RB). While a chest X-ray is the first-line imaging investigation in patients presenting with symptoms suggestive of lung cancer, it has a high positive predictive value (PPV) even after negative X-ray findings, which calls into question its value as part of a potential national screening programme. CT lowers the mortality for high-risk patients when compared to X-ray and certain scoring systems, such as the Brock model can guide the need for further imaging, like PET-CT, which has high sensitivity and specificity for diagnosing solitary pulmonary nodules as malignant, as well as for assessing small cell lung cancer spread. In practice, PET-CT is offered to everyone whose lung cancer is to be treated with a curative intent. In contrast, MRI is only recommended for isolated distant metastases. Similarly, ultrasound imaging is not used for diagnosis of lung cancer but can be useful when there is suspicion of intrathoracic lymph node involvement. Ultrasound imaging in the form of endobronchial ultrasonography (EBUS) is often used to aid tissue sampling, yet the diagnostic value of this technique varies widely between studies. RB is another novel technique that offers an alternative way to biopsy lesions, but further research on it is necessary. Lastly, thoracic surgical biopsies, particularly minimally invasive video-assisted techniques, have been used increasingly to aid in diagnosis and staging.

Dosimetric comparison of 3DCRT and IMRT in radical chemoradiotherapy of squamous cell carcinoma esophagus.

BACKGROUND: Radical chemoradiation is the standard of treatment for locally advanced squamous cell carcinoma of esophagus and for patients with operable disease, but who are medically unfit or unwilling for surgery. As the esophagus is a central organ, the planning target volume (PTV) is central, lies close to the spinal cord and heart, and is surrounded by the lung, which is a radiosensitive organ. Irradiation of these critical structures is reduced by the use of three-dimensional conformal radiation therapy (3DCRT). Intensity-modulated radiation therapy (IMRT) has the potential to improve the uniformity of dose distribution to the tumor and reduce the dose received by surrounding normal tissues. AIM AND OBJECTIVES: 1. To compare the dose distribution, conformity, and homogeneity indices in radical radiotherapy of squamous cell carcinoma of esophagus using 3DCRT and IMRT techniques 2. To compare the doses received by critical structures such as heart, lung, spinal cord, and liver. MATERIALS AND METHODS: All cases of squamous cell carcinoma esophagus treated with radical chemoradiation to a dose of 50 Gy in 25 fractions using 3DCRT technique from January 2018 to July 2019 were included. IMRT plans were generated for these cases.The parameters that represent dose distribution to the target volume and the dose received by the organs at risk were obtained from the dose-volume histogram. The difference in the mean values of the parameters between the two techniques was calculated. The statistical significance of the difference was determined using Student's t-test and Wilcoxon signed-rank test. RESULTS: The volume of PTV receiving 105% and 107% of prescribed dose was significantly lower with IMRT (3.540% and 0.008%, respectively) compared to 3DCRT (7.654% and 0.623%). The homogeneity index was better with IMRT (0.088 vs. 0.107) than 3DCRT. Conformity index was found to be better with IMRT (1.149 vs. 1.573). Mean heart dose (18.216 vs. 24.591 Gy) and the volume of heart receiving 30 Gy were reduced with IMRT. The volume of lung receiving 20 Gy and the volume receiving 5 Gy were not significantly different between 3DCRT and IMRT. Maximum dose to spinal cord was similar with 3DCRT and IMRT. CONCLUSIONS: IMRT avoids areas of excessive irradiation within the PTV. IMRT improves dose conformity to the target volume and homogeneity of dose distribution within the PTV. The cardiac dose is significantly reduced with IMRT. The mean lung dose remains similar to 3DCRT. There is no significant increase in the volume of lung receiving low-dose radiation with IMRT.

The Developing Field of Scaffold-Free Tissue Engineering for Articular Cartilage Repair.

Articular cartilage is critical for proper joint mobility as it provides a smooth and lubricated surface between articulating bones and allows for transmission of load to underlying bones. Extended wear or injury of this tissue can result in osteoarthritis, a degenerative disease affecting millions across the globe. Because of its low regenerative capacity, articular cartilage cannot heal on its own and effective treatments for injured joint restoration remain a challenge. Strategies in tissue engineering have been demonstrated as potential therapeutic approaches to regenerate and repair damaged articular cartilage. Although many of these strategies rely on the use of an exogenous three-dimensional scaffolds to regenerate cartilage, scaffold-free tissue engineering provides numerous advantages over scaffold-based methods. This review highlights the latest advancements in scaffold-free tissue engineering for cartilage and the potential for clinical translation. Impact statement Although scaffolds are often incorporated into cartilage tissue engineering strategies as a three-dimensional architecture conducive to tissue formation, scaffold-free approaches are increasingly recognized for their ability to better recapitulate the native tissue formation process. Recent advancements in scaffold-free tissue engineering and success in clinical trials demonstrate the potential of these techniques to serve as viable therapies for repairing and restoring damaged cartilage.

Oligomeric Aß1-42 Induces an AMD-Like Phenotype and Accumulates in Lysosomes to Impair RPE Function.

Alzheimer's disease-associated amyloid beta (Aß) proteins accumulate in the outer retina with increasing age and in eyes of age-related macular degeneration (AMD) patients. To study Aß-induced retinopathy, wild-type mice were injected with nanomolar human oligomeric Aß1-42, which recapitulate the Aß burden reported in human donor eyes. In vitro studies investigated the cellular effects of Aß in endothelial and retinal pigment epithelial (RPE) cells. Results show subretinal Aß-induced focal AMD-like pathology within 2 weeks. Aß exposure caused endothelial cell migration, and morphological and barrier alterations to the RPE. Aß co-localized to late-endocytic compartments of RPE cells, which persisted despite attempts to clear it through upregulation of lysosomal cathepsin B, revealing a novel mechanism of lysosomal impairment in retinal degeneration. The rapid upregulation of cathepsin B was out of step with the prolonged accumulation of Aß within lysosomes, and contrasted with enzymatic responses to internalized photoreceptor outer segments (POS). Furthermore, RPE cells exposed to Aß were identified as deficient in cargo-carrying lysosomes at time points that are critical to POS degradation. These findings imply that Aß accumulation within late-endocytic compartments, as well as lysosomal deficiency, impairs RPE function over time, contributing to visual defects seen in aging and AMD eyes.

Nail Changes in Leprosy: Onychoscopy Evaluation.

CONTEXT: Repeated trauma involving extremities (in the setting of peripheral neuropathy) and poor vascularity that impairs wound healing are important causes of disability and deformity in leprosy patients. Nail changes can serve as indicators of trophic changes due to leprosy. AIMS: To describe the onychoscopy findings in leprosy cases and to identify any specific findings in leprosy patients in comparison to controls. SETTINGS AND DESIGN: The first 30 leprosy patients and 30 age and sex-matched controls who attended our tertiary care center from 1 August 2018 were included in this cross-sectional study. MATERIALS AND METHODS: Onychoscopy examination of all fingernails was performed at 50× magnification using dinolite dermoscope AM4113ZT under non-polarizing light to document surface changes and under polarizing light to document pigmentation and vascular changes. STATISTICAL ANALYSIS: The observed nail changes in cases and controls were compared using Pearson's Chi-square test. RESULTS: Statistically significant association with leprosy was found for pitting, onycholysis, melanonychia, transverse lines, nail pallor, and onychauxis. Nail pallor was unique to leprosy patients. LIMITATIONS: Small sample size and not evaluating toenails were the major limitations of the study. CONCLUSIONS: Studies with large sample size are needed to assess the significance of nail pallor as a specific onychoscopy finding in leprosy.

The right ventricular fibroblast secretome drives cardiomyocyte dedifferentiation.

RATIONALE: In virtually all models of heart failure, prognosis is determined by right ventricular (RV) function; thus, understanding the cellular mechanisms contributing to RV dysfunction is critical. Whole organ remodeling is associated with cell-specific changes, including cardiomyocyte dedifferentiation and activation of cardiac fibroblasts (Cfib) which in turn is linked to disorganization of cytoskeletal proteins and loss of sarcomeric structures. However, how these cellular changes contribute to RV function remains unknown. We've previously shown significant organ-level RV dysfunction in a large animal model of pulmonary hypertension (PH) which was not mirrored by reduced function of isolated cardiomyocytes. We hypothesized that factors produced by the endogenous Cfib contribute to global RV dysfunction by generating a heterogeneous cellular environment populated by dedifferentiated cells. OBJECTIVE: To determine the effect of Cfib conditioned media (CM) from the PH calf (PH-CM) on adult rat ventricular myocytes (ARVM) in culture. METHODS AND RESULTS: Brief exposure (<2 days) to PH-CM results in rapid, marked dedifferentiation of ARVM to a neonatal-like phenotype exhibiting spontaneous contractile behavior. Dedifferentiated cells maintain viability for over 30 days with continued expression of cardiomyocyte proteins including TnI and α-actinin yet exhibit myofibroblast characteristics including expression of α-smooth muscle actin. Using a bioinformatics approach to identify factor(s) that contribute to dedifferentiation, we found activation of the PH Cfib results in a unique transcriptome correlating with factors both in the secretome and with activated pathways in the dedifferentiated myocyte. Further, we identified upregulation of periostin in the Cfib and CM, and demonstrate that periostin is sufficient to drive cardiomyocyte dedifferentiation. CONCLUSIONS: These data suggest that paracrine factor(s) released by Cfib from the PH calf signal a phenotypic transformation in a population of cardiomyocytes that likely contributes to RV dysfunction. Therapies targeting this process, such as inhibition of periostin, have the potential to prevent RV dysfunction.

Atypical PRES with diffusion restriction or neurotoxicity- ? part of same spectrum-after oxaliplatin (FOLFOX-4 regimen) for colonic cancer.

Atypical features of Posterior reversible encephalopathy syndrome (PRES) (diffusion restriction, involvement of corpus callosum & white matter tracts along posterior limbs of internal capsule) were seen in a patient after oxaliplatin administration (FOLFOX- 4 regimen). Findings were most obvious on diffusion weighted images, similar to acute methotrexate neurotoxicity, and resolved completely on follow up.

Medication Safety Principles and Practice in CKD.

Ensuring patient safety is a priority of medical care because iatrogenic injury has been a primary concern. Medications are an important source of medical errors, and kidney disease is a thoroughfare of factors threatening safe administration of medicines. Principal among these is reduced kidney function because almost half of all medications used are eliminated via the kidney. Additionally, kidney patients often suffer from multimorbidity, including diabetes, hypertension, and heart failure, with a range of prescribers who often do not coordinate treatments. Patients with kidney disease are also susceptible to further kidney injury and metabolic derangements from medications, which can worsen the disease. In this review, we will present the key issues and threats to safe medication use in kidney disease, with a focus on predialysis CKD, as the scope of medication safety in ESKD and transplantation are unique and deserve their own consideration. We discuss drugs that need to be avoided or dose modified, and review the complications of a range of medications routinely administered in CKD, as these also call for cautious use.

The Role of PCSK9 Inhibitors in the Treatment of Hypercholesterolemia.

OBJECTIVE: To evaluate the efficacy, safety, and cost-effectiveness of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors and describe its place in therapy for the treatment of hypercholesterolemia. DATA SOURCES: A search of MEDLINE, CINAHL, and Clinicaltrials.gov was performed from January 2012 to March 2018 to identify literature pertaining to PCSK9 inhibitors using pre-specified search terms. Additional references were identified from citations of the literature. STUDY SELECTION AND DATA EXTRACTION: Only articles in English were reviewed. Phase II, phase III, pooled, post hoc, and cardiovascular (CV) trials were included. Cost-effectiveness studies and conference materials were also reviewed. DATA SYNTHESIS: All trials evaluating alirocumab and evolocumab demonstrated significant low-density lipoprotein cholesterol (LDL-C) lowering versus comparators. Two trials revealed a decrease in the major adverse cardiovascular events (MACE) end point with PCSK9 inhibitor use; 1 of these 2 trials revealed a decrease in all-cause mortality with alirocumab use. No significant safety concerns apart from injection site reactions were noted. Despite these results, 4 cost-effectiveness analyses failed to meet acceptable thresholds. Relevance to Patient Care and Clinical Practice: This review describes the most up-to-date evidence regarding PCSK9 inhibitors. A discussion on LDL-C lowering potential, effect on CV events and mortality, safety considerations, feasibility of administration, and cost are included to guide clinicians on future use. CONCLUSION: The PCSK9 inhibitor drug class is an effective LDL-C lowering option for patients with the highest risk of CVD events and high LDL-C despite the use of statin therapy. For more widespread use, significant cost reductions are needed.

Radical Treatment of Rectal Cancer in Elderly Is Feasible than Feared: Results from a Tertiary Care Centre.

The thought of subjecting an elderly patient with rectal cancer to protocol-based neoadjuvant chemoradiation (NACTRT), surgery and adjuvant chemotherapy is sought with fear due to their multiple comorbidities and impaired functional status associated with the process of ageing. Hence, many a times the treatment is compromised and it is a fact that this subgroup of patients is underrepresented in most of the clinical trials. This study was aimed at analysing the perioperative and oncologic outcomes after protocol-based treatment of rectal cancer in the elderly patients, defined here as those with age ≥70 years. Prospective analysis of medical records of rectal cancer patients was done who were ≥70 years of age and were diagnosed and treated at Regional Cancer Centre (RCC), Thiruvanathapuram from 2008 to 2012. In this 5-year period, a total of 339 rectal cancer patients underwent surgery as part of multimodality treatment with curative intent. Of them, 75 patients were ≥70 years of age. Half of them had one or more comorbidities (54%) and majority were locally advanced at presentation (77%). Forty-seven (62%) cases received NACTRT and all of them tolerated RT dose (50.4 Gy) without modification. Anterior resection (AR) was performed in 48 (64%) and abdominoperineal resection (APR) in remaining. Diverting stoma was made in four; of which three remained permanent. Two colostomies were performed for delayed leaks. Three patients (4%) died within 30 days due to leak, sepsis and cardiopulmonary causes. Two thirds (49/75) received adjuvant chemotherapy (ACT) but only 55% of them (27/49) could complete all the cycles without dose modification. The median survival was 28 months. The 3-year disease-free survival (DFS) and overall (OS) were 80.1 and 83.9%, respectively. There were 11 distant recurrences including two locoregional recurrences. The morbidity and mortality of multimodality therapy is reasonable to proceed with radical treatment with curative intent in the elderly patients with rectal cancer.

Lixisenatide (Adlyxin): A Once-Daily Incretin Mimetic Injection for Type-2 Diabetes.

Lixisenatide (Adlyxin), a once-daily incretin mimetic injection for type-2 diabetes.

Fibronectin fibrils regulate TGF-ß1-induced Epithelial-Mesenchymal Transition.

Epithelial-Mesenchymal Transition (EMT) is a dynamic process through which epithelial cells transdifferentiate from an epithelial phenotype into a mesenchymal phenotype. Previous studies have demonstrated that both mechanical signaling and soluble growth factor signaling facilitate this process. One possible point of integration for mechanical and growth factor signaling is the extracellular matrix. Here we investigate the role of the extracellular matrix (ECM) protein fibronectin (FN) in this process. We demonstrate that inhibition of FN fibrillogenesis blocks activation of the Transforming Growth Factor-Beta (TGF-ß) signaling pathway via Smad2 signaling, decreases cell migration and ultimately leads to inhibition of EMT. Results show that soluble FN, FN fibrils, or increased contractile forces are insufficient to independently induce EMT. We further demonstrate that inhibition of latent TGF-ß1 binding to FN fibrils via either a monoclonal blocking antibody against the growth factor binding domain of FN or through use of a FN deletion mutant that lacks the growth factor binding domains of FN blocks EMT progression, indicating a novel role for FN in EMT in which the assembly of FN fibrils serves to localize TGF-ß1 signaling to drive EMT.

Do Contemporary Randomized Controlled Trials Meet ESMO Thresholds for Meaningful Clinical Benefit?

Background: The European Society for Medical Oncology (ESMO) recently released a magnitude of clinical benefit scale (ESMO-MCBS) for systemic therapies for solid cancers. Here, we evaluate contemporary randomized controlled trials (RCTs) against the proposed ESMO thresholds for meaningful clinical benefit. Methods: RCTs evaluating systemic therapy for breast cancer, nonsmall cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic cancer published 2011-2015 were reviewed. Data were abstracted regarding trial characteristics and outcomes, and these were applied to the ESMO-MCBS. We also determined whether RCTs were designed to detect an effect that would meet clinical benefit as defined by the ESMO-MCBS. Results: About 277 eligible RCTs were included (40% breast, 31% NSCLC, 22% CRC, 6% pancreas). Median sample size was 532 and 83% were funded by industry. Among all 277 RCTs, the experimental therapy was statistically superior to the control arm in 138 (50%) trials: results of only 31% (43/138) of these trials met the ESMO-MCBS clinical benefit threshold. RCTs with curative intent were more likely to meet clinically meaningful thresholds than those with palliative intent [61% (19/31) versus 22% (24/107), P < 0.001]. Among the 226 RCTs for which the ESMO-MCBS could be applied, 31% (70/226) were designed to detect an effect size that could meet ESMO-MCBS thresholds. Conclusion: Less than one-third of contemporary RCTs with statistically significant results meet ESMO thresholds for meaningful clinical benefit, and this represents only 15% of all published trials. Investigators, funding agencies, regulatory agencies, and industry should adopt more stringent thresholds for meaningful benefit in the design of future RCTs.

The transcription factor, Nuclear factor, erythroid 2 (Nfe2), is a regulator of the oxidative stress response during Danio rerio development.

Development is a complex and well-defined process characterized by rapid cell proliferation and apoptosis. At this stage in life, a developmentally young organism is more sensitive to toxicants as compared to an adult. In response to pro-oxidant exposure, members of the Cap'n'Collar (CNC) basic leucine zipper (b-ZIP) transcription factor family (including Nfe2 and Nfe2-related factors, Nrfs) activate the expression of genes whose protein products contribute to reduced toxicity. Here, we studied the role of the CNC protein, Nfe2, in the developmental response to pro-oxidant exposure in the zebrafish (Danio rerio). Following acute waterborne exposures to diquat or tert-buytlhydroperoxide (tBOOH) at one of three developmental stages, wildtype (WT) and nfe2 knockout (KO) embryos and larvae were morphologically scored and their transcriptomes sequenced. Early in development, KO animals suffered from hypochromia that was made more severe through exposure to pro-oxidants; this phenotype in the KO may be linked to decreased expression of alas2, a gene involved in heme synthesis. WT and KO eleutheroembryos and larvae were phenotypically equally affected by exposure to pro-oxidants, where tBOOH caused more pronounced phenotypes as compared to diquat. Comparing diquat and tBOOH exposed embryos relative to the WT untreated control, a greater number of genes were up-regulated in the tBOOH condition as compared to diquat (tBOOH: 304 vs diquat: 148), including those commonly found to be differentially regulated in the vertebrate oxidative stress response (OSR) (e.g. hsp70.2, txn1, and gsr). When comparing WT and KO across all treatments and times, there were 1170 genes that were differentially expressed, of which 33 are known targets of the Nrf proteins Nrf1 and Nrf2. More specifically, in animals exposed to pro-oxidants a total of 968 genes were differentially expressed between WT and KO across developmental time, representing pathways involved in coagulation, embryonic organ development, body fluid level regulation, erythrocyte differentiation, and oxidation-reduction, amongst others. The greatest number of genes that changed in expression between WT and KO occurred in animals exposed to diquat at 2h post fertilization (hpf). Across time and treatment, there were six genes (dhx40, cfap70, dnajb9b, slc35f4, spi-c, and gpr19) that were significantly up-regulated in KO compared to WT and four genes (fhad1, cyp4v7, nlrp12, and slc16a6a) that were significantly down-regulated. None of these genes have been previously identified as targets of Nfe2 or the Nrf family. These results demonstrate that the zebrafish Nfe2 may be a regulator of both primitive erythropoiesis and the OSR during development.