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Jiali Ji,1 Xiaolan Dai,2 Sai-Ching Jim Yeung,3 Xuexin He11Department of Medical Oncology, The 2nd Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang, People’s Republic of China; 2Department of Pharmacy, School of Medicine, Shantou University, Shantou, Guangdong, People’s Republic of China; 3Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USAAbstract: Long non-coding RNAs (lncRNAs) have shown potential as a biomarker in the diagnosis and prognosis in multiple cancers. LncRNAs are dysregulated in various cancers, playing either oncogenic or tumor suppressive roles. Emerging evidences have proved that the growth arrest-specific 5 (GAS5) lncRNA can function as a tumor suppressor in several cancers. LncRNA GAS5 is downregulated in many types of cancer, regulating cellular processes such as cell proliferation, apoptosis and invasion. The low level of GAS5 expression often elevates capacity of proliferation and predicts poorer prognosis in some cancers. This review aims to summarize the recent published literature on the biogenesis, regulation mechanism and function of GAS5 in different types of cancers and explore its potential for cancer diagnosis, prognosis and treatment.Keywords: lncRNA, GAS5, tumor suppressor, tumor

Purpose: To compare visual outcomes of endophthalmitis following intravitreal injections (IVIs) and cataract extraction by causative organism., Methods: Searches in Cochrane Central Register of Controlled Trials, MEDLINE, and Embase identified articles reporting visual outcomes by causative organisms in post-IVI and cataract extraction endophthalmitis cases from January 2010 to February 2022. A random-effects meta-analysis compared visual improvement among endophthalmitis cases caused by causative organisms., Results: Eighty-five out of 3,317 retrieved studies were included. The highest degree of visual acuity improvement in both post-IVI and postcataract extraction endophthalmitis was seen in cases caused by coagulase-negative staphylococci, followed by gram-negative organisms and other gram-positive organisms such as streptococci and enterococci. Culture-negative cases showed more visual acuity improvement than culture-positive cases in post-IVI endophthalmitis. These results remained consistent when accounting for endophthalmitis treatment, IVI type, condition requiring IVI treatment, follow-up period, and initial preprocedural visual acuity., Conclusion: Coagulase-negative staphylococci and gram-negative organisms show the most visual acuity improvement in both post-IVI and postcataract extraction endophthalmitis. Other gram-positive organisms such as streptococci and enterococci are associated with less visual improvement. This updated systematic review and meta-analysis revealed that the results of the Endophthalmitis Vitrectomy Study are consistent decades later despite advancements in surgical practices and the evolution of microorganisms over time.

Background & Aims: Early detection of esophageal squamous cell carcinoma (ESCC) will facilitate curative treatment. We aimed to establish a microRNA (miRNA) signature derived from salivary extracellular vesicles and particles (EVPs) for early ESCC detection and prognostication., Methods: Salivary EVP miRNA expression was profiled in a pilot cohort (n = 54) using microarray. Area under the receiver operator characteristic curve (AUROC) and least absolute shrinkage and selector operation regression analyses were used to prioritize miRNAs that discriminated patients with ESCC from controls. Using quantitative reverse transcription polymerase chain reaction, the candidates were measured in a discovery cohort (n = 72) and cell lines. The prediction models for the biomarkers were derived from a training cohort (n = 342) and validated in an internal cohort (n = 207) and an external cohort (n = 226)., Results: The microarray analysis identified 7 miRNAs for distinguishing patients with ESCC from control subjects. Because 1 was not always detectable in the discovery cohort and cell lines, the other 6 miRNAs formed a panel. A signature of this panel accurately identified patients with all-stage ESCC in the training cohort (AUROC = 0.968) and was successfully validated in 2 independent cohorts. Importantly, this signature could distinguish patients with early-stage (stage Ⅰ/Ⅱ) ESCC from control subjects in the training cohort (AUROC = 0.969, sensitivity = 92.00%, specificity = 89.17%) and internal (sensitivity = 90.32%, specificity = 91.04%) and external (sensitivity = 91.07%, specificity = 88.06%) validation cohorts. Moreover, a prognostic signature based on the panel was established and efficiently predicted the high-risk cases with poor progression-free survival and overall survival., Conclusions: The salivary EVP-based 6-miRNA signature can serve as noninvasive biomarkers for early detection and risk stratification of ESCC. Chinese Clinical Trial Registry, ChiCTR2000031507., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Both obstructive sleep apnea (OSA) and non-alcoholic fatty liver disease (NAFLD) are prevalent within obese individuals. We aimed to investigate the effects of intermittent hypoxia (IH), a clinical feature of OSA, on hepatic expression of fatty acid translocase (CD36) in relation to liver injury in lean and diet-induced obese mice., Methods: Four-week-old male C57BL/6J mice were randomized to standard diet (SD) or high fat (HF) diet groups. At 13-week-old, all mice were exposed to either air or IH (IH30; thirty hypoxic episodes per hour) for four weeks. We assessed liver injury through lipid profile, oxidative and inflammatory stress, histological scoring and hepatic CD36 expression., Results: In lean mice, IH elevated serum and hepatic triglyceride and free fatty acid (FFA) levels, in line with upregulation of hepatic CD36 expression and myeloperoxidase (MPO)-positive cells in support of inflammatory infiltrates along with increase in serum malondialdehyde (MDA), C-X-C motif chemokine ligand 1(CXCL-1) and monocyte chemoattractant protein-1 (MCP-1). In diet-induced obese mice, an increase in hepatic alanine transaminase (ALT) activity, serum and hepatic levels of lipid parameters and inflammatory markers, serum MDA level, hepatic expressions of CD36 and α-smooth muscle actin (α-SMA), and MPO-positive cells was observed. IH potentiated hepatic ALT activity, serum CXCL-1 and hepatic interleukin-6 (IL-6), in line with inflammatory infiltrates, but paradoxically, reduced hepatic FFA level and hepatic CD36 expression, compared to obese mice without IH exposure. However, IH further augmented diet-induced liver steatosis and fibrosis as shown by histological scores., Conclusion: This study contributes to support that IH featuring OSA may lead to liver injury via differential regulation of hepatic CD36 expression in lean and diet-induced obese mice., Competing Interests: Conflicts of interest The authors have no Conflicts of interest to declare., (Copyright © 2022 Chang Gung University. Published by Elsevier B.V. All rights reserved.)

Chemotherapy-related cognitive impairment (CRCI) or "chemo brain" is a devastating neurotoxic sequela of cancer-related treatments, especially for the elderly individuals. Here we show that PTPRO, a tyrosine phosphatase, is highly enriched in the hippocampus, and its level is tightly associated with neurocognitive function but declined significantly during aging. To understand the protective role of PTPRO in CRCI, a mouse model was generated by treating Ptpro-/- female mice with doxorubicin (DOX) because Ptpro-/- female mice are more vulnerable to DOX, showing cognitive impairments and neurodegeneration. By analyzing PTPRO substrates that are neurocognition-associated tyrosine kinases, we found that SRC and EPHA4 are highly phosphorylated/activated in the hippocampi of Ptpro-/- female mice, with increased sensitivity to DOX-induced CRCI. On the other hand, restoration of PTPRO in the hippocampal CA3 region significantly ameliorate CRCI in Ptpro-/- female mice. In addition, we found that the plant alkaloid berberine (BBR) is capable of ameliorating CRCI in aged female mice by upregulating hippocampal PTPRO. Mechanistically, BBR upregulates PTPRO by downregulating miR-25-3p, which directly targeted PTPRO. These findings collectively demonstrate the protective role of hippocampal PTPRO against CRCI.

Sepsis remains a leading cause of death for humans and currently has no pathogenesis-specific therapy. Hampered progress is partly due to a lack of insight into deep mechanistic processes. In the past decade, deciphering the functions of small noncoding miRNAs in sepsis pathogenesis became a dynamic research topic. To screen for new miRNA targets for sepsis therapeutics, we used samples for miRNA array analysis of PBMCs from patients with sepsis and control individuals, blood samples from 2 cohorts of patients with sepsis, and multiple animal models: mouse cecum ligation puncture-induced (CLP-induced) sepsis, mouse viral miRNA challenge, and baboon Gram+ and Gram- sepsis models. miR-93-5p met the criteria for a therapeutic target, as it was overexpressed in baboons that died early after induction of sepsis, was downregulated in patients who survived after sepsis, and correlated with negative clinical prognosticators for sepsis. Therapeutically, inhibition of miR-93-5p prolonged the overall survival of mice with CLP-induced sepsis, with a stronger effect in older mice. Mechanistically, anti-miR-93-5p therapy reduced inflammatory monocytes and increased circulating effector memory T cells, especially the CD4+ subset. AGO2 IP in miR-93-KO T cells identified important regulatory receptors, such as CD28, as direct miR-93-5p target genes. In conclusion, miR-93-5p is a potential therapeutic target in sepsis through the regulation of both innate and adaptive immunity, with possibly a greater benefit for elderly patients than for young patients.

Studies with static faces find that upper face halves are more easily recognized than lower face halves-an upper-face advantage. However, faces are usually encountered as dynamic stimuli, and there is evidence that dynamic information influences face identity recognition. This raises the question of whether dynamic faces also show an upper-face advantage. The objective of this study was to examine whether familiarity for recently learned faces was more accurate for upper or lower face halves, and whether this depended upon whether the face was presented as static or dynamic. In Experiment 1, subjects learned a total of 12 faces--6 static images and 6 dynamic video-clips of actors in silent conversation. In experiment 2, subjects learned 12 faces, all dynamic video-clips. During the testing phase of Experiments 1 (between subjects) and 2 (within subjects), subjects were asked to recognize upper and lower face halves from either static images and/or dynamic clips. The data did not provide evidence for a difference in the upper-face advantage between static and dynamic faces. However, in both experiments, we found an upper-face advantage, consistent with prior literature, for female faces, but not for male faces. In conclusion, the use of dynamic stimuli may have little effect on the presence of an upper-face advantage, especially when the static comparison contains a series of static images, rather than a single static image, and is of sufficient image quality. Future studies could investigate the influence of face gender on the presence of an upper-face advantage., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: To describe a case of proliferative retinopathy as the presenting manifestation of chronic myeloid leukemia in a patient with poorly controlled diabetes mellitus (DM). Undiagnosed chronic myeloid leukemia in a patient with pre-existing poorly controlled DM is rarely encountered but must be recognized to treat appropriately with systemic chemotherapy. Significant fundus finding overlaps with DM making the recognition of chronic myeloid leukemia challenging., Methods: Case report., Results: Fundoscopy revealed scattered dot-blot hemorrhages, venous beading, and numerous Roth spots in all quadrants, in both eyes. In the right eye, there was also a vitreous hemorrhage with evidence of neovascularization near the inferior arcade. Intravenous fluorescein angiography showed significant peripheral capillary nonperfusion without evidence of exudation in both eyes. No macular edema was observed on optical coherence tomography. A review of systems and physical examination was negative for constitutional symptoms, lymphadenopathy, organomegaly, and other symptoms. Retinal findings prompted a complete blood count, which revealed significant leukocytosis. A bone marrow biopsy confirmed a diagnosis of chronic myeloid leukemia. Systemic chemotherapy and pan-retinal photocoagulation successfully normalized the leukocyte count and resolved the vitreous hemorrhage and neovascularization., Conclusion: The presence of numerous Roth spots in all quadrants, extensive areas of capillary nonperfusion on intravenous fluorescein angiography, and neovascularization in the absence of exudation or macular edema should prompt investigations to rule out hematologic disorders.

The choroid plays an important role in various ocular pathologies and retinal blood supply. There is a knowledge gap on how the choroid is affected by systemic and topical medications. Systemic medications that affect microvasculature elsewhere in the body can also affect the microvasculature of the choroid. This review summarizes current knowledge on associations between systemic and topical medications and changes in choroidal thickness (CT). This review included 71 studies on mydriatics/cycloplegics, intraocular pressure (IOP)-lowering therapies, antihypertensives, adrenergic antagonists, statins, corticosteroids, hydroxychloroquine, isotretinoin, hormonal contraceptives, phosphodiesterase inhibitors, antipsychotics, antineoplastic agents, ethanol, caffeine and nicotine. IOP-lowering therapies, atropine eye drops, and systemic administration of β blockers and ethanol are associated with a significant increase in CT. Cyclopentolate and phenylephrine are associated with a CT reduction. Systemic medications that decrease CT include caffeine and nicotine. Tropicamide, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, statins, corticosteroids, hydroxychloroquine and hormonal contraceptives have mixed findings. CT increase associated with IOP-lowering therapies is possibly achieved by enhancing aqueous humour flow to the choroid thus elevating choroidal blood flow and thickness. CT changes appear to be independent from systemic blood pressure changes, suggesting that a significant association with an antihypertensive could be due to an idiosyncratic drug property. Statins and candesartan decrease macrophage accumulation and intercellular adhesion molecule 1 expression in the choroid. The choroid and its response to various disease processes and systemic medication can be further investigated to improve patient care, particularly in patients with choroid and retina pathologies., (© 2022 British Pharmacological Society.)

Stoma creations are common procedures in surgical specialties. They can be created either as a temporary or a permanent measure. Despite advancements in surgical technique and stoma care, complications are common. Patients experiencing stoma-related complications often present to the emergency department. Emergency physicians are not expected to be stoma experts, yet they are often the first point of contact for patients experiencing stoma-related complications. Accordingly, emergency physicians should be familiar with the types of stomas and complications and emergencies associated with them so that they can appropriately address the problems related to stomas. This article will provide a review of emergencies and complications associated with ileostomies, colostomies, and urostomies., (© 2022. The Author(s).)

Introduction: Midshaft clavicular fractures are common amongst young adults. Conservative or surgical treatment for definitive fracture management has been widely debate, both with their pros and cons. Previous meta-analyses compared the clinical outcomes between conservative and surgical treatment options of midshaft clavicular fractures but failed to elucidate any difference in functional improvement. We postulate that functional improvement after fracture union plateaus and the clinical outcome after treatment varies at different time points. This meta-analysis will focus on the synthesis comparison of outcomes at early, short-term results (3 months), intermediate-term (6 to 12 months) and long-term (>24 months) clinical outcomes., Methods: A systematic search was done on databases (Pubmed, Embase, Medline, Cochrane) in June 2021. Search keywords were: midshaft clavicular fractures and clinical trials. Clinical trials fulfilling the inclusion criteria were selected for comparison and the clinical outcomes of midshaft clavicular fractures using surgical and non-surgical interventions in terms of improvement in the Disabilities of the Arm, Shoulder and Hand (DASH) score, Constant-Murley Score (CMS), time to union and risk ratio of treatment related complications were analysed in correlation with post-treatment timeframe., Results: Of the 3094 patients of mean age 36.7 years in the 31 selected studies, surgical intervention was associated with improved DASH score (standard-mean difference SMD -0.22, 95% CI -0.36 to -0.07, p = 0.003; mean difference MD -1.72, 95% CI -2.93 to -0.51, p = 0.005), CMS (SMD 0.44, 95% CI 0.17-0.72, p = 0.001; MD 3.64, 95% CI 1.09 to 6.19, p = 0.005), time to union (non-adjusted SMD -2.83, 95% CI -4.59 to -1.07, p = 0.002; adjusted SMD -0.69, 95% CI -0.97 to -0.41, p<0.001) and risk ratio of bone-related complications including bone non-union, malunion and implant failure (0.21, 95% CI 0.1 to 0.42; p<0.001). Subgroup analysis based on time period after treatment showed that surgical intervention was far superior in terms of improved DASH score at the intermediate-term results (6-12 months later, SMD -0.16, 95% CI -0.30 to -0.02, p = 0.02; and long term results (>24 months SMD -4.24, 95% CI -7.03 to -1.45, p = 0.003) and CMS (>24 months, SMD 1.03, 95% CI 0.39 to 1.68, p = 0.002; MD 5.77, 95% CI 1.63 to 9.91, p = 0.006). Surgical outcome is independent of fixation with plates or intra-medullary nails., Conclusion: Surgical intervention was associated with better clinical outcomes compared with non-surgical approach for midshaft clavicular fractures in terms of improvement in functional scores DASH, CMS, time to union and fracture related complications, although not to the minimal clinically significant difference. Benefits in the long-term functional improvements are more pronounced., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Emergency department (ED) visits by patients with cancer frequently end in hospitalization. As concerns about ED and hospital crowding increase, observation unit care may be an important strategy to deliver safe and efficient treatment for eligible patients. In this investigation, we compared the prevalence and clinical characteristics of cancer patients who received observation unit care with those who were admitted to the hospital from the ED., Methods: We performed a multicenter prospective cohort study of patients with cancer presenting to an ED affiliated with one of 18 hospitals of the Comprehensive Oncologic Emergency Research Network (CONCERN) between March 1, 2016 and January 30, 2017. We compared patient characteristics with the prevalence of observation unit care usage, hospital admission, and length of stay., Results: Of 1051 enrolled patients, 596 (56.7%) were admitted as inpatients, and 72 (6.9%) were placed in an observation unit. For patients admitted as inpatients, 23.7% had a length of stay ≤2 days. The conversion rate from observation to inpatient was 17.1% (95% CI 14.6-19.4) among those receiving care in an observation unit. The average observation unit length of stay was 14.7 h. Patient factors associated ED disposition to observation unit care were female gender and low Charlson Comorbidity Index., Conclusion: In this multicenter prospective cohort study, the discrepancy between observation unit care use and short inpatient hospitalization may represent underutilization of this resource and a target for process change., (© 2021 by the Society for Academic Emergency Medicine.)

Purpose: The purpose of this study was to compare functional and anatomical outcomes after epiretinal membrane (ERM) peeling with internal limiting membrane (ERM/ILM) peeling and without for the treatment of idiopathic ERM., Design: Systematic review and meta-analysis., Methods: A comprehensive search of Cochrane CENTRAL, MEDLINE Ovid, and Embase Ovid for randomized controlled trials comparing ERM/ILM with ERM was performed. Two independent reviewers selected papers and extracted data. Methodological quality was assessed using the Cochrane Risk of Bias (RobVis) tool. Data was analyzed using RevMan 5.3. Quality of body of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach., Results: Seven studies reporting 387 eyes overall were included. A total of 207 eyes (53%) received ERM/ILM. A total of 180 (47%) received ERM. Post-operative visual acuities (logMAR) were not significantly different between ERM/ILM and ERM, with a mean difference (MD) of 0.02 (95% confidence interval [CI]: -0.04 to 0.09; P = .45; I 2 = 42%; n = 101) at 1 month; 0.03 (95% CI: -0.01 to 0.06; P = .11, I 2  = 15%; n = 299; High Certainty of Evidence) at 3 months; 0.01 (95% CI: -0.03 to 0.04; P = .72; I 2  = 21%; n = 317; High Certainty of Evidence) at 6 months; and 0.01 (95% CI: -0.02 to 0.04; P = .49; I 2  = 39%; n = 234) at 12 months post-operatively. ERM/ILM was significantly associated with lower ERM recurrence at 6-12 months with a relative risk of 0.16 (95% CI: 0.04-0.64; P = .01; I 2  = 0%; n = 155; Moderate certainty of evidence) and an increased central macular thickness (micrometers) at 12 months with an MD of 20.53 (95% CI: 4.96-36.09; P = .01; I 2  = 12%; n = 234)., Conclusions: ERM/ILM and ERM result in similar visual acuity despite subtle differences in anatomical outcomes (central macular thickness). ERM/ILM is associated with a significantly lower rate of ERM recurrence at 6-12 months post-operatively and should be considered where recurrence prevention is the treatment priority., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: To compare the visual outcomes after prompt pars plana vitrectomy (PPV) with tap biopsy and intravitreal antimicrobial injection to treat postinjection and postsurgery endophthalmitis., Methods: The Cochrane Central Register of Controlled Trials, Ovid MEDLINE, and Ovid Embase databases were searched for articles published between January 2010 and November 2020. Two independent reviewers selected articles and extracted data. We analyzed data in RevMan 5.3 and assessed methodological quality using the Cochrane ROBINS-I tool. The mean improvement in visual outcome was compared between PPV and intravitreal antimicrobial injection as a relative risk of improving ≥2 lines and a mean logarithm of the minimal angle of resolution difference in improvement., Results: Fifteen retrospective case series (1,355 eyes), of which 739 eyes (55%) received intravitreal antimicrobial injection and 616 (45%) received PPV as initial treatment, were included. The overall relative risk of improving 2 or more lines in PPV in comparison with intravitreal antimicrobial injection was 1.04 (95% CI 0.88-1.23; P = 0.61; I2 = 0%) with a mean difference of 0.04 (95% CI -0.18 to 0.27; P = 0.69; I2 = 0%). The results stayed robust when subgroup analysis based on causative procedure for endophthalmitis was performed., Conclusion: Intravitreal antimicrobial injection is noninferior to PPV for the treatment of postcataract operation, postinjection, and post-PPV endophthalmitis.

Affective-motivational disturbances are highly inconsistent in animal pain models. The reproducibility of the open-field test in assessing anxiety, malaise or disability remains controversial despite its popularity. While traumatic, persistent or multiregional pain models are commonly considered more effective in inducing negative affect or functional impairment, the early psychobehavioral changes before pain chronification are often underexplored. Here, we aimed to clarify the fundamental relationship between hypernociception and passive distress-like behavior using a model of transient inflammatory pain. To minimize latent confounders and increase data consistency, male C57BL/6N mice were habituated to the open-field arena 6 times before receiving the unilateral intraplantar injection of prostaglandin E2 (PGE2) or vehicle. Open-field (40-min exploration) and nociceptive behavior were evaluated repeatedly along the course of hypernociception in both wild-type and transgenic mice with a known pronociceptive phenotype. To reduce subjectivity, multivariate open-field behavioral outcomes were analyzed by statistical modeling based on exploratory factor analyses, which yielded a 2-factor solution. Within 3 hr after PGE2 injection, mice developed significantly reduced center exploration (factor 1) and a marginally significant increase in their habituation tendency (factor 2), which were not apparent in vehicle-injected mice. The behavioral passivity generally improved as hypernociception subsided. Therefore, transient inflammatory irritation is sufficient to suppress mouse open-field exploratory activity. The apparent absence of late affective-motivational changes in some rodents with prolonged hypernociception may not imply a lack of preceding or underlying neuropsychological alterations. Procedural pain after invasive animal experiments, however small, should be assessed and adequately controlled as a potential research confounder., (© 2021 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Transcription-induced chimeric RNAs are an emerging area of research into molecular signatures for disease biomarker and therapeutic target development. Despite their importance, little is known for chimeric RNAs-relevant roles and the underlying mechanisms for cancer pathogenesis and progression. Here we describe a unique ASTN2-PAPPA antisense chimeric RNA (A-P as chiRNA) that could be the first reported chimeric RNA derived from the splicing of exons and intron antisense of two neighboring genes, respectively. Aberrant A-P as chiRNA level in ESCC tissues was associated with tumor progression and patients' outcome. In vitro and in vivo studies demonstrated that A-P as chiRNA aggravated ESCC metastasis and enhanced stemness through modulating OCT4. Mechanistic studies demonstrated that ERK5-mediated non-canonical PAF1 activity was required for A-P as chiRNA-induced cancer malignancy. The study defined an undocumented function of chimeric RNAs in aggravating cancer stemness and metastasis., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: This work describes a stepwise surgical approach to draining choroidal detachments and 2 cases for which this approach was used., Methods: The first step involves insertion of an anterior chamber maintainer and a nonvalved 23- or 25-gauge trocar cannula at the highest peak of hemorrhagic choroidal detachment (as determined using B-scan ultrasonography), 6 to 8 mm from and angled 20° to 30° toward the limbus. The second step involves removal of the trocar to expose the sclerotomy. Alternatively, the second step can be insertion of a second trocar. The third step involves the creation of a small focal peritomy around the preexisting sclerotomy and enlargement of the preexisting sclerotomy into a radial sclerotomy. Progression between steps only occurs if prior steps did not provide adequate drainage., Results: Two cases of appositional hemorrhagic choroidal detachments in hypotonic eyes were successfully resolved by this stepwise approach. In case 1, a choroidal detachment developed after a corneal ulcer perforation. The hemorrhagic choroidal detachment in case 1 was resolved with steps 1 and 2, and an unnecessary scleral cutdown was avoided. In case 2, a choroidal detachment developed after a trabeculectomy. The detachment in case 2 required progression to step 3, extension of the trocar insertion site into a radial sclerotomy., Conclusions: This stepwise approach should be considered to reduce excessive manipulation of the globe and conjunctiva in hemorrhagic and serous choroidal detachments that warrant surgical intervention., Competing Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2021.)

Background: Holistic biopsychosocial care has been underemphasized in perioperative pathway designs. The importance and a cost-effective way of implementing biopsychosocial care to improve postoperative pain and facilitate surgical convalescence are not well established, despite the recent popularization of Enhanced Recovery After Surgery (ERAS) programs., Objective: We have explored the evidence and rationale of environmental enrichment (EE) as a complementary multimodal psychosocial care pathway to reduce postoperative pain, optimize patient recovery and improve existing weaknesses in surgical care., Methods: We conducted a database search to identify and grade potential EE techniques for their evidence quality and consistency in the management of acute postoperative pain, perioperative anxiety and the etiologically comparable acute procedural or experimental pain., Findings and Conclusions: The introduction of music, virtual reality, educational information, mobile apps, or elements of nature into the healthcare environment can likely improve patients' experience of surgery. Compared with traditional psychological interventions, EE modalities are voluntary, therapist-sparing and more economically sustainable. We have also discussed practical strategies to integrate EE within the perioperative workflow. Through a combination of sensory, motor, social and cognitive modalities, EE is an easily implementable patient-centered approach to alleviate pain and anxiety in surgical patients, create a more homelike recovery environment and improve quality of life., Competing Interests: The authors declare no conflict of interests., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Patients with esophageal cancer often experience clinically relevant deterioration of quality of life (QOL) after esophagectomy owing to malnutrition, lack of physical exercise, and psychological symptoms., Objective: This study aimed to evaluate the feasibility, safety, and efficacy of a comprehensive intervention model using a mobile health system (CIMmH) in patients with esophageal cancer after esophagectomy., Methods: Twenty patients with esophageal cancer undergoing the modified McKeown surgical procedure were invited to join the CIMmH program with both online and offline components for 12 weeks. The participants were assessed before surgery and again at 1 and 3 months after esophagectomy. QOL, depressive symptoms, anxiety, stress, nutrition, and physical fitness were measured., Results: Of the 20 patients, 16 (80%) completed the program. One month after esophagectomy, patients showed significant deterioration in overall QOL (P=.02), eating (P=.005), reflux (P=.04), and trouble with talking (P<.001). At the 3-month follow-up, except for pain (P=.02), difficulty with eating (P=.03), dry mouth (P=.04), and trouble with talking (P=.003), all other QOL dimensions returned to the preoperative level. There were significant reductions in weight (P<.001) and BMI (P=.02) throughout the study, and no significant changes were observed for physical fitness measured by change in the 6-minute walk distance between baseline and the 1-month follow-up (P=.22) or between baseline and the 3-month follow-up (P=.52). Depressive symptoms significantly increased 1 month after surgery (P<.001), while other psychological measures did not show relevant changes. Although there were declines in many measures 1 month after surgery, these were much improved at the 3-month follow-up, and the recovery was more profound and faster than with traditional rehabilitation programs., Conclusions: The CIMmH was feasible and safe and demonstrated encouraging efficacy testing with a control group for enhancing recovery after surgery among patients with esophageal cancer in China., Trial Registration: Chinese Clinical Trial Registry (ChiCTR-IPR-1800019900); http://www.chictr.org.cn/showprojen.aspx?proj=32811., (©Chao Cheng, Rainbow Tin Hung Ho, Yan Guo, Mengting Zhu, Weixiong Yang, Yiran Li, Zhenguo Liu, Shuyu Zhuo, Qi Liang, Zhenghong Chen, Yu Zeng, Jiali Yang, Zhanfei Zhang, Xu Zhang, Aliza Monroe-Wise, Sai-Ching Yeung. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 18.08.2020.)

The choroid is a vascular network that supplies the bulk of the retina's oxygen and nutrient supply. Prior studies have associated changes in the thickness of the choroid with the presence of various cardiovascular diseases. This is the first review that summarizes current knowledge on the relationship between choroidal thickness and cardiovascular diseases while highlighting important findings. Acute hypertension increases choroidal thickness. Chronic hypertension and heart failure may decrease choroidal thickness, but controversy exists. Both coronary artery disease and carotid artery stenosis result in decreased choroidal thickness and blood flow. Carotid endarterectomy may reverse these changes. Choroidal thickening in early stages of carotid stenosis may arise from mechanisms compensating for ischemia. Hyperlipidemia is linked to choroidal thickening, while caffeine intake is linked to choroidal thinning. The effects of smoking and exercise are mixed. Changes in choroidal thickness have been linked to cardiovascular disease. Clarity regarding these changes could lead to the use of choroidal thickness changes as a noninvasive screening or prognostic test for pathological cardiovascular changes. Future studies should also investigate the effect of cardiovascular disease treatments on the choroid., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The accurate detection of cancer-associated venous thromboembolism (VTE) can avoid unnecessary diagnostic imaging or laboratory tests., Objective: We sought to determine clinical and cancer-related risk factors of VTE that can be used as predictors for oncology patients presenting to the emergency department (ED) with suspected VTE., Methods: We retrospectively analyzed all consecutive patients who presented with suspicion of VTE to The University of Texas MD Anderson Cancer Center ED between January 1, 2009, and January 1, 2013. Logistic regression models were used to identify risk factors that were associated with VTE. The ability of these factors to predict VTE was externally validated using a second cohort of patients who presented to King Hussein Cancer Center ED between January 1, 2009, and January 1, 2016., Results: Cancer-related covariates associated with the occurrence of VTE were high-risk cancer type (odds ratio [OR] 3.64 [95% confidence interval {CI} 2.37-5.60], p < 0.001), presentation within 6 months of the cancer diagnosis (OR 1.92 [95% CI 1.62-2.28], p < 0.001), active cancer (OR 1.35 [95% CI 1.10-1.65], p = 0.003), advanced stage (OR 1.40 [95% CI 1.01-1.94], p = 0.044), and the presence of brain metastasis (OR 1.73 [95% CI 1.32-2.27], p < 0.001). When combined, these factors along with other clinical factors showed high prediction performance for VTE in the external validation cohort., Conclusions: Cancer risk group, presentation within 6 months of cancer diagnosis, active and advanced cancer, and the presence of brain metastases along with other related clinical factors can be used to predict VTE in patients with cancer presenting to the ED., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

The set size effect during visual search indexes the effects of processing load and thus the efficiency of perceptual mechanisms. Our goal was to investigate whether individuals with developmental prosopagnosia show increased set size effects when searching faces for face identity and how this compares to search for face expression. We tested 29 healthy individuals and 13 individuals with developmental prosopagnosia. Participants were shown sets of three to seven faces to judge whether the identities or expressions of the faces were the same across all stimuli or if one differed. The set size effect was the slope of the linear regression between the number of faces in the array and the response time. Accuracy was similar in both controls and prosopagnosic participants. Developmental prosopagnosic participants displayed increased set size effects in face identity search but not in expression search. Single-participant analyses reveal that 11 developmental prosopagnosic participants showed a putative classical dissociation, with impairments in identity but not expression search. Signal detection theory analysis showed that identity set size effects were highly reliable in discriminating prosopagnosic participants from controls. Finally, the set size ratios of same to different trials were consistent with the predictions of self-terminated serial search models for control participants and prosopagnosic participants engaged in expression search but deviated from those predictions for identity search by the prosopagnosic cohort. We conclude that the face set size effect reveals a highly prevalent and selective perceptual inefficiency for processing face identity in developmental prosopagnosia.

Background: Acupuncture intervention in actual practice is rarely reported and may be different from that applied in acupuncture research. Objectives: To review acupuncture practice in an integrative medicine clinic and characterize the association between targeted symptoms, traditional Chinese medicine (TCM) diagnosis, and acupoint selection. Methods: We reviewed outpatient acupuncture records from March 2016 to April 2018. Statistical analyses were applied to characterize referral symptoms and associated TCM diagnosis as well as acupoint selection. Results: The final analysis included 5393 acupuncture records (1264 patients). Twelve TCM diagnosis components were identified in the referral symptoms of pain, neuropathy, xerostomia, and hot flashes. Pain was associated with 78 different TCM diagnoses (combinations of TCM diagnosis components). Total of 217 different acupoints were used in the acupuncture treatments (1739) for neuropathy. The acupoint yintang was used in 73.8% of the visits for neuropathy, yet only in 26.5% ( P < .001) of the treatments when patients had a TCM diagnosis of qi deficiency, qi stagnation, and blood stagnation. Similarly, both consistencies and variations were seen in acupoint selection with each targeted symptom and its associated TCM diagnoses. Conclusions: TCM diagnosis was not homogeneous among acupuncture treatments for a single referral symptom. In contrast to most of the research on acupuncture for symptom control, there were considerable variations in acupoint selection among treatments for the same symptom in a clinical setting. Future research is needed to examine the clinical relevance of a fixed intervention structure in acupuncture research and the value of individualized acupuncture treatment.

Cancer cell stemness (CCS) plays critical roles in both malignancy maintenance and metastasis, yet the underlying molecular mechanisms are far from complete. Although the importance of SOX2 in cancer development and CCS are well recognized, the role of MTA3 in these processes is unknown. In this study, we used esophageal squamous cell carcinoma (ESCC) as a model system to demonstrate that MTA3 can repress both CCS and metastasis in vitro and in vivo. Mechanistically, by forming a repressive complex with GATA3, MTA3 downregulates SOX2OT, subsequently suppresses the SOX2OT/SOX2 axis, and ultimately represses CCS and metastasis. More importantly, MTA3 low /SOX2 high is associated with poor prognosis and could serve as an independent prognostic factor. These findings altogether indicate that MTA3/SOX2OT/SOX2 axis plays an indispensable role in CCS. Therefore, this axis could be potentially used in cancer stratification and serves as a therapeutic target., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: This study was to investigate the degree of susceptibility to intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), between the two mice inbred lines C57BL/6N (6N) and C57BL/6J (6J)., Materials and Methods: Four-week old male mice of 6N and 6J substrains (n = 8) were randomized to standard diet (SD) group or high fat (HF) diet group. At the age of 13-week, all two groups of mice were subjected to either air or IH (IH30; thirty hypoxic events per hour) for one week., Key Findings: All mice fed with HF diet exhibited obesity with more body weight and fat mass (percentage to body weight) gain. IH reduced serum LDL, HDL and total cholesterol levels in lean 6J mice. In obese mice, IH lowered obesity-induced serum total cholesterol level in 6J substrain but raised further in 6N substrain. Furthermore, IH caused elevation of serum FFA and MDA levels, and pro-inflammatory cytokines MCP-1 and IL-6 levels in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) of lean 6J but not lean 6N mice. There was reduced number of adipocytes and elevation of macrophages in SAT and VAT of HF-induced obese mice of both substrains. IH led to increased number of adipocytes and macrophages in SAT of lean 6J mice., Significance: The genetic difference between 6N and 6J mice may have direct impact on metabolic and inflammatory responses after IH. Therefore, attention must be given for the selection of C57BL mice substrains in the experimental IH-exposed mouse model., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Clinical evidence suggests that Parkinson's Disease (PD) patients are risk averse. Dopaminergic therapy has been reported to increase risk tolerance, but the underlying mechanisms are unclear. Some studies have suggested an amplification of subjective reward value, consistent with the role of dopamine in reward value coding. Others have reported value-independent risk enhancement. We evaluated the value-dependence of the effects of PD and its therapy on risk using tasks designed to sensitively measure risk over a wide range of expected values., Method: 36 patients with idiopathic PD receiving levodopa monotherapy and 36 healthy matched controls performed two behavioural economic tasks aimed at quantifying 1) risk tolerance/aversion in the gain frame and 2) valuation of potential gains relative to losses. PD patients performed the tasks on and off their usual dose of levodopa in randomized order; controls performed the same tasks twice., Results: Relative to the controls, unmedicated PD patients showed significant value-independent risk aversion in the gain frame, which was normalized by levodopa. PD patients did not differ from controls in their valuation of gains relative to losses. However, across both tasks and regardless of medication, choices of the patients were more determined by expected values of the prospects than those of controls., Conclusion: Dopamine deficiency in PD was associated with risk aversion, and levodopa promoted riskier choice in a value-independent manner. PD patients also showed an increased sensitivity to expected value, which was independent of levodopa and does not appear to result directly from dopamine deficiency., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Acupuncture is a recognized integrative modality for managing hot flashes. However, data regarding predictors for response to acupuncture in cancer patients experiencing hot flashes are limited. We explored associations between patient characteristics, including traditional Chinese medicine (TCM) diagnosis, and treatment response among cancer patients who received acupuncture for management of hot flashes., Methods: We reviewed acupuncture records of cancer outpatients with the primary reason for referral listed as hot flashes who were treated from March 2016 to April 2018. Treatment response was assessed using the hot flashes score within a modified Edmonton Symptom Assessment Scale (0-10 scale) administered immediately before and after each acupuncture treatment. Correlations between TCM diagnosis, individual patient characteristics, and treatment response were analyzed., Results: The final analysis included 558 acupuncture records (151 patients). The majority of patients were female (90%), and 66% had breast cancer. The median treatment response was a 25% reduction in the hot flashes score. The most frequent TCM diagnosis was qi stagnation (80%) followed by blood stagnation (57%). Older age ( P = .018), patient self-reported anxiety level ( P = .056), and presence of damp accumulation in TCM diagnosis ( P = .047) were correlated with greater hot flashes score reduction., Conclusions: TCM diagnosis and other patient characteristics were predictors of treatment response to acupuncture for hot flashes in cancer patients. Future research is needed to further explore predictors that could help tailor acupuncture treatments for these patients.

Background: Lipid dysregulation is a classical risk factor for cardiovascular disease (CVD), yet scanty evidence existed regarding cardiac lipid metabolism that is directly related to heart damage. Recently, the relationship between dyslipidemia and pro-inflammatory insults has led to further understanding on the CVD-predisposing effects of dyslipidemia. The aims of the present study were to investigate whether high-fat high-cholesterol (HFHC) diet-induced hyperlipidemia would cause heart damage and to study the potential role of local cardiac lipid dysregulation in the occurrence of cellular injury., Methods: Male Sprague-Dawley rats were divided into normal chow or HFHC diet groups, and sacrificed after 2 or 4 weeks, respectively. Lipid peroxidation marker level was measured. Lipid parameters in the rat hearts were detected. Cardiac damage was evaluated., Results: HFHC diet increased serum levels of cholesterol and free fatty acids (FFAs) and led to systemic oxidative stress and pro-inflammatory status. Cardiac lipid dysregulation, which was characterized by elevated levels of cholesterol and adipocyte (A)- and heart (H)-fatty acid binding proteins (FABPs), occurred after HFHC diet for 4 weeks. Cardiac damage was further evident with elevated circulating H-FABP levels, increased cardiac interstitial fibrosis and the loss of troponin I., Conclusion: Our data demonstrated that HFHC diet led to systemic and cardiac lipid dysregulation, accompanied by systemic oxidative and pro-inflammatory stresses, and these may finally cooperate to cause a series of pathological changes of the heart tissue. Our findings suggest that maintenance of lipid regulation may be essential in the prevention of heart damage.

Neuropathic pain inflicts tremendous biopsychosocial suffering for patients worldwide. However, safe and effective treatment of neuropathic pain is a prominent unmet clinical need. Environmental enrichment (EE) is an emerging cost-effective nonpharmacological approach to alleviate neuropathic pain and complement rehabilitation care. We present here a review of preclinical studies in ascertaining the efficacy of EE for neuropathic pain. Their proposed mechanisms, including the suppression of ascending nociceptive signaling to the brain, enhancement of the descending inhibitory system, and neuroprotection of the peripheral and central nervous systems, may collectively reduce pain perception and improve somatic and emotional functioning in neuropathic pain. The current evidence offers critical insights for future preclinical research and the translational application of EE in clinical pain management., (© 2018 World Institute of Pain.)

Background: Cigarette smoking is the leading cause of chronic obstructive pulmonary disease. (-)-Epigallocatechin-3-gallate (EGCG), the major catechins in Chinese green tea, has been studied for its anti-oxidative and anti-inflammatory properties in cell and animal models. In this study, we aimed to analyze the effects of EGCG on cigarette smoke (CS)-induced airway inflammation and mucus secretion in the CS-exposed rat model. Methods: Male Sprague-Dawley rats were randomly divided into either sham air (SA) or CS exposure. EGCG (50 mg/kg b.wt.) was given by oral gavage every other day in both SA and CS-exposed animals. Oxidative stress and inflammatory markers were determined in serum and/or bronchoalveolar lavage fluid by biochemical assays or ELISA. Lung morphological changes were examined by Periodic Acid-Schiff, Masson's Trichrome staining and immunohistochemical analysis. Western blot analysis was performed to explore the effects of EGCG on epidermal growth factor receptor (EGFR)-mediated signaling pathway. Results: (-)-Epigallocatechin-3-gallate treatment attenuated CS-induced oxidative stress, lung cytokine-induced neutrophil chemoattractant-1 release and neutrophil recruitment. CS exposure caused an increase in the number of goblet cells in line with MUC5AC upregulation, and increased lung collagen deposition, which were alleviated in the presence of EGCG. In addition, CS-induced phosphorylation of EGFR in rat lung was abrogated by EGCG treatment. Conclusion: (-)-Epigallocatechin-3-gallate treatment ameliorated CS-induced oxidative stress and neutrophilic inflammation, as well as airway mucus production and collagen deposition in rats. The present findings suggest that EGCG has a therapeutic effect on chronic airway inflammation and abnormal airway mucus production probably via inhibition of EGFR signaling pathway.

The strong relationship between cigarette smoking and cardiovascular disease (CVD) has been well-documented, but the mechanisms by which smoking increases CVD risk appear to be multifactorial and incompletely understood. Mesenchymal stem cells (MSCs) are regarded as an important candidate for cell-based therapy in CVD. We hypothesized that MSCs derived from induced pluripotent stem cell (iPSC-MSCs) or bone marrow (BM-MSCs) might alleviate cigarette smoke (CS)-induced cardiac injury. This study aimed to investigate the effects of BM-MSCs or iPSC-MSCs on CS-induced changes in serum and cardiac lipid profiles, oxidative stress and inflammation as well as cardiac function in a rat model of passive smoking. Male Sprague-Dawley rats were randomly selected for exposure to either sham air (SA) as control or 4% CS for 1 h per day for 56 days. On day 29 and 43, human adult BM-MSCs, iPSC-MSCs or PBS were administered intravenously to CS-exposed rats. Results from echocardiography, serum and cardiac lipid profiles, cardiac antioxidant capacity, cardiac pro- and anti-inflammatory cytokines and cardiac morphological changes were evaluated at the end of treatment. iPSC-MSC-treated group showed a greater effect in the improvement of CS-induced cardiac dysfunction over BM-MSCs-treated group as shown by increased percentage left ventricular ejection fraction and percentage fractional shortening, in line with the greater reversal of cardiac lipid abnormality. In addition, iPSC-MSCs administration attenuated CS-induced elevation of cardiac pro-inflammatory cytokines as well as restoration of anti-inflammatory cytokines and anti-oxidative markers, leading to ameliorate cardiac morphological abnormalities. These data suggest that iPSC-MSCs on one hand may restore CS-induced cardiac lipid abnormality and on the other hand may attenuate cardiac oxidative stress and inflammation via inhibition of CS-induced NF-κB activation, leading to improvement of cardiac remodeling and dysfunction. Thus, iPSC-MSCs may be a promising candidate in cell-based therapy to prevent cardiac complications in smokers.

A series of new platinum Pt(II) compounds possessing a bidentate leaving ligand modified from oxaliplatin has been synthesized, with one of the oxygen ligating atom substituted for a sulphur atom (resulting in a Pt-NNSO coordination core structure). The general structures are R,R-diaminocyclohexane (DACH)-Pt-(methylthio)acetic acid (K4) and DACH-Pt-(thiophenylacetic acid) (K4 derivatives). Substitution of an electron donating or withdrawing group at the ortho or para position on the phenyl ring of K4 derivatives was found to affect the complexes' stability, reactivity with the biological molecules (5'-guanosine monophosphate (5'-GMP) and L-methionine (L-Met)) and anticancer activity. 1 H NMR experiments demonstrated that Pt-NNSO complexes formed a mixture of mono- and diadduct with 5'-GMP in various ratios, which are different from the classical Pt drugs (forming mainly diadduct). In addition, all of the K4 derivatives with improved lipophilicity are less deactivated by L-Met in comparison to cisplatin (CDDP) and oxaliplatin. Biological assessments showed that all Pt-NNSO complexes are less toxic than CDDP in normal porcine kidney cells and are minimally affected by drug resistance. Some of the new compounds also displayed comparable anticancer activity to CDDP or better than carboplatin in a few cancer cell lines. The lower reactivity of the Pt-NNSO compounds than CDDP towards thiol molecules, presumably leading to less efflux in resistant cancer cells, and the ability to inhibit autophagy were believed to allow the new compounds to be less affected by Pt resistance., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Mesenchymal stem cells (MSCs) have emerged as a potential cell-based therapy for pulmonary emphysema in animal models. Our previous study demonstrated that human induced pluripotent stem cell-derived MSCs (iPSC-MSCs) were superior over bone marrow-derived MSCs (BM-MSCs) in attenuating cigarette smoke (CS)-induced airspace enlargement possibly through mitochondrial transfer. This study further investigated the effects of iPSC-MSCs on inflammation, apoptosis, and proliferation in a CS-exposed rat model and examined the effects of the secreted paracrine factor from MSCs as another possible mechanism in an in vitro model of bronchial epithelial cells. Rats were exposed to 4% CS for 1 hr daily for 56 days. At days 29 and 43, human iPSC-MSCs or BM-MSCs were administered intravenously. We observed significant attenuation of CS-induced elevation of circulating 8-isoprostane and cytokine-induced neutrophil chemoattractant-1 after iPSC-MSC treatment. In line, a superior capacity of iPSC-MSCs was also observed in ameliorating CS-induced infiltration of macrophages and neutrophils and apoptosis/proliferation imbalance in lung sections over BM-MSCs. In support, the conditioned medium (CdM) from iPSC-MSCs ameliorated CS medium-induced apoptosis/proliferation imbalance of bronchial epithelial cells in vitro. Conditioned medium from iPSC-MSCs contained higher level of stem cell factor (SCF) than that from BM-MSCs. Deprivation of SCF from iPSC-MSC-derived CdM led to a reduction in anti-apoptotic and pro-proliferative capacity. Taken together, our data suggest that iPSC-MSCs may possess anti-apoptotic/pro-proliferative capacity in the in vivo and in vitro models of CS-induced airway cell injury partly through paracrine secretion of SCF., (© 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)

The plasma membrane-associated tyrosine phosphatase PTPRO is frequently transcriptionally repressed in cancers and signifies poor prognosis of breast cancer patients. In this study, deletion of Ptpro in MMTV-Erbb2 transgenic mice dramatically shortened the mammary tumor latency and accelerated tumor growth due to loss of Ptpro within the breast cancer cells but not in surrounding tissue as confirmed by hetero-transplantation studies. Both in vitro and in vivo data demonstrated that the phosphatase activity was required for the inactivation of ERBB2 and its downstream signaling. PTPRO regulated the phosphorylation status of ERBB2 at Y1248. Co-immunoprecipitation and proximity ligation assay (Duolink) indicated that PTPRO directly physically interacted with ERBB2. Moreover, PTPRO phosphatase activity shortened the half-life of ERBB2 by increasing endocytotic degradation. PTPRO reexpression by demethylation treatment using 5-azacytidine reduced the proliferation and colony formation potential in ERBB2-positive breast cancer cells. Taken together, PTPRO inhibited ERBB2-driven breast cancer through dephosphorylation leading to dual effects of ERBB2 signaling suppression and endosomal internalization of ERBB2, Therefore, reexpression of PTPRO may be a potential therapy for ERBB2-overexpressing breast cancer.

Studies suggest that a word-length effect of up to 160 ms/letter distinguishes hemianopic dyslexia from pure alexia. However, partial preservation of central vision is common in right hemianopia, but its effects on single-word reading are unknown. Eighteen healthy subjects read single words with a gaze-contingent right hemianopia simulation that varied the degree of central sparing. Mean reading onset time declined with small degrees of central sparing, but the word-length effect did not decrease until sparing exceeded 3.15°. We next evaluated the effects of font size. Effects of central sparing were constant when expressed in number of letters, with a decline in word-length effect beginning as sparing approached 4 letters. We conclude that the effects of central sparing on mean reading onset time and the word-length effect are distinct. We provide diagnostic word-length criteria for discriminating between pure alexia and hemianopic dyslexia with various degrees of central sparing.

Background: The frequency of delirium among patients with cancer presenting to the emergency department (ED) is unknown. The purpose of this study was to determine delirium frequency and recognition by ED physicians among patients with advanced cancer presenting to the ED of The University of Texas MD Anderson Cancer Center., Methods: The study population was a random sample of English-speaking patients with advanced cancer who presented to the ED and met the study criteria. All patients were assessed with the Confusion Assessment Method (CAM) to screen for delirium and with the Memorial Delirium Assessment Scale (MDAS) to measure delirium severity (mild, ≤15; moderate, 16-22; and severe, ≥23). ED physicians were also asked whether their patients were delirious., Results: Twenty-two of the 243 enrolled patients (9%) had CAM-positive delirium, and their median MDAS score was 14 (range, 9-21 [30-point scale]). The median age of the enrolled patients was 62 years (range, 19-89 years). Patients with delirium had a poorer performance status than patients without delirium (P < .001); however, the 2 groups did not differ in other characteristics. Ten of the 99 patients who were 65 years old or older (10%) had CAM-positive delirium, whereas 12 of the 144 patients younger than 65 years (8%) did (P = .6). According to the MDAS scores, delirium was mild in 18 patients (82%) and moderate in 4 patients (18%). Physicians correctly identified delirium in 13 of the CAM-positive delirious patients (59%)., Conclusions: Delirium is relatively frequent and is underdiagnosed by physicians in patients with advanced cancer who are visiting the ED. Further research is needed to identify the optimal screening tool for delirium in ED. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2918-2924. © 2016 American Cancer Society., (© 2016 American Cancer Society.)

Background: Intratumoral heterogeneity presents a major obstacle to the widespread implementation of precision medicine. The authors assessed the origin of intratumoral heterogeneity in nonseminomatous germ cell tumor of the testis (NSGCT) and identified distinct tumor subtypes and a potentially lethal phenotype., Methods: In this retrospective study, all consecutive patients who had been diagnosed with an NSGCT between January 2000 and December 2010 were evaluated. The histologic makeup of primary tumors and the clinical course of disease were determined for each patient. A Fine and Gray proportional hazards regression analysis was used to determine the prognostic risk factors, and the Gray test was used to detect differences in the cumulative incidence of cancer death. In a separate prospective study, next-generation sequencing was performed on tumor samples from 9 patients to identify any actionable mutations., Results: Six hundred fifteen patients were included in this study. Multivariate analysis revealed that the presence of yolk sac tumor in the primary tumor (P = .0003) was associated with an unfavorable prognosis. NSGCT could be divided into 5 subgroups. Patients in the yolk sac-seminoma subgroup had the poorest clinical outcome (P = .0015). These tumors tended to undergo somatic transformation (P < .0001). Among the 9 NSGCTs that had a yolk sac tumor phenotype, no consistent gene mutation was detected., Conclusions: The current data suggest that intratumoral heterogeneity is caused in part by differentiation of pluripotent progenitor cells. Integrated or multimodal therapy may be effective at addressing intratumoral heterogeneity and treating distinct subtypes as well as a potentially lethal phenotype of NSGCT. Cancer 2016;122:1836-43. © 2016 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes., (© 2016 American Cancer Society.)

Three molecular targeted tyrosine kinase inhibitors (TKI) were conjugated to classical platinum-based drugs with an aim to circumvent TKI resistance, predominately mediated by the emergence of secondary mutations on oncogenic kinases. The hybrids were found to maintain specificity towards the same oncogenic kinases as the original TKI. Importantly, they are remarkably less affected by TKI resistance, presumably due to their unique structure and the observed dual mechanism of anticancer activity (kinase inhibition and DNA damage). The study is also the first to report the application of a hybrid drug approach to switch TKIs from being efflux transporter substrates into non-substrates. TKIs cannot penetrate into the brain for treating metastases because of efflux transporters at the blood brain barrier. The hybrids were found to escape drug efflux and they accumulate more than the original TKI in the brain in BALB/c mice. Further development of the hybrid compounds is warranted.

Purpose: The identification of patients at high risk for poor outcomes may allow for earlier palliative care and prevent futile interventions. We examined the association of presenting symptoms on risk of intensive care unit (ICU) admission and hospital death among patients with cancer admitted through an emergency department (ED)., Methods: We queried MD Anderson Cancer Center databases for all patients who visited the ED in 2010. Presenting symptoms, ICU admissions, and hospital deaths were reviewed; patient data analyzed; and risk factors for ICU admission and hospital mortality identified., Results: The main presenting symptoms were pain, fever, and respiratory distress. Of the patients with cancer who visited the ED, 5,362 (58%) were admitted to the hospital at least once (range, 1 to 13 admissions), 697 (13%) were admitted to the ICU at least once, and 587 (11%) died during hospitalization (31% of 233 patients with hematologic malignancies and 27% of 354 patients with solid tumors died in the ICU; P < .001). In multivariable logistic regression, presenting symptoms of respiratory distress or altered mental status; lung cancer, leukemia, or lymphoma; and nonwhite race were independent predictors of hospital death. Patients who died had a longer median length of hospital stay than patients discharged alive (14 v 6 days for hematologic malignancies and 7 v 5 days for solid tumors; P < .001)., Conclusion: Patients with cancer admitted through an ED experience high ICU admission and hospital mortality rates. Patients with advanced cancer and respiratory distress or altered mental status may benefit from palliative care that avoids unnecessary interventions., (Copyright © 2016 by American Society of Clinical Oncology.)

Background: Septic shock may be associated with myocardial damage; however, the prognostic value of cardiac enzymes in cancer patients with septic shock is unknown. In this study, we evaluated the prognostic significance of cardiac enzymes in combination with established prognostic factors in predicting the 7-day mortality rate of patients with septic shock, and we constructed a new scoring system, Septic Oncologic Patients in Emergency Department (SOPED), which includes cardiac enzymes, to predict 7-day mortality rates., Methods and Findings: We performed a retrospective cohort study of 375 adult cancer patients with septic shock who visited the emergency department of a comprehensive cancer center between 01/01/2004 and 12/31/2013. The 7-day and 28-day mortality rates were 19.7% and 37.6%, respectively. The creatine kinase myocardial band fraction and troponin-I were significantly higher in patients who died in ≤7 days and ≤28 days than in those who did not. In Cox regression models, troponin-I >0.05 ng/mL plus Predisposition, Infection, Response, and Organ Failure (PIRO2011) or Mortality in Emergency Department Sepsis (MEDS) score was a significant predictor of survival for ≤7 days. With our new SOPED scoring system, the receiver operating characteristic area under the curve was 0.836, higher than those for PIRO2011 and MEDS., Conclusions: Troponin-I >0.05 ng/mL was an important predictor of short-term mortality (≤7 days). The SOPED scoring system, which incorporated troponin-I, was more prognostically accurate than were other scores for 7-day mortality. Large multicenter studies are needed to verify our results and prospectively validate the prognostic performance of the SOPED score.

Background: The concurrence of ectopic adrenocorticotropic hormone (ACTH) syndrome (ectopic Cushing syndrome) and cancer is uncommon in the emergency department (ED) setting, but a constellation of nonspecific signs and symptoms can suggest the presence of Cushing syndrome., Case Report: A 65-year-old woman with diabetes visited the ED complaining of severe weight loss, generalized weakness, and hypokalemia. She was treated for hypokalemia and thrush. She was found to have a lung mass with a large pleural effusion. Upon discovery of the suspected malignancy, the patient was referred to the ED of a comprehensive cancer center, where she was diagnosed with ectopic Cushing syndrome and admitted to the hospital for further evaluation and treatment. WHY SHOULD THE EMERGENCY PHYSICIAN BE AWARE OF THIS?: The emergency physician should be able to recognize Cushing syndrome in cancer patients so that the paraneoplastic syndrome can be managed to avoid complications during cancer treatment., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Genetic susceptibility plays an important role in the risk of developing pain in individuals with cancer. As a complex trait, multiple genes underlie this susceptibility. We used gene network analyses to identify novel target genes associated with pain in patients newly diagnosed with squamous cell carcinoma of the head and neck (HNSCC)., Results: We first identified 36 cancer pain-related genes (i.e., focus genes) from 36 publications based on a literature search. The Ingenuity Pathway Analysis (IPA) analysis identified additional genes that are functionally related to the 36 focus genes through pathway relationships yielding a total of 82 genes. Subsequently, 800 SNPs within the 82 IPA-selected genes on the Illumina HumanOmniExpress-12v1 platform were selected from a large-scale genotyping effort. Association analyses between the 800 candidate SNPs (covering 82 genes) and pain in a patient cohort of 1368 patients with HNSCC (206 patients with severe pain vs. 1162 with non-severe pain) showed the highest significance for MAPK1/ERK2, a gene belonging to the MAP kinase family (rs8136867, p value = 8.92 × 10(-4); odds ratio [OR] = 1.33, 95 % confidence interval [CI]: 1.13-1.58). Other top genes were PIK3C2G (a member of PI3K [complex], rs10770367, p value = 1.10 × 10(-3); OR = 1.46, 95 % CI: 1.16-1.82), TCRA (the alpha chain of T-cell receptor, rs6572493, p value = 2.84 × 10(-3); OR = 0.70, 95 % CI: 0.55-0.88), PDGFC (platelet-derived growth factor C, rs6845322, p value = 4.88 × 10(-3); OR = 1.32, 95 % CI: 1.09-1.60), and CD247 (a member of CD3, rs2995082, p value = 7.79 × 10(-3); OR = 0.76, 95 % CI: 0.62-0.93)., Conclusions: Our findings provide novel candidate genes and biological pathways underlying pain in cancer patients. Further study of the variations of these candidate genes could inform clinical decision making when treating cancer pain.