Search

Regional lymph nodes metastasis is an important predictor for survival outcome and the indicator for postoperative adjuvant chemotherapy in patients with colorectal cancer (CRC) patient. Even the advance in the adjuvant chemotherapeutic regimen, the 5-year distant metastasis and survival are still unsatisfied. Here, we evaluate the clinical significance of single-nucleotide polymorphisms on TLR1 and TLR2, which are the receptors for HMGB1 that is the hallmark for immunogenic cell death (ICD), in patients with stage II-III colon carcinoma (COAD). We found patients with high cytosolic HMGB1 are associated with survival outcome in stage III COAD patients who received adjuvant chemotherapy. Moreover, patients with TLR1-N248S polymorphism (rs4833095) may influence the therapeutic efficacy of adjuvant chemotherapy, suggesting TLR1-N248S is an independent prognostic factor for locally advanced colon carcinoma patients. Moreover, patient bearing TLR1-N248S polymorphism had high risk of distant metastasis after first-line adjuvant chemotherapeutic regimen with 5 year by multivariate COX analysis [HR=1.694, 95%CI=1.063-2.698, p=0.027]. We found that defective TLR1 impaired TLR1/2 signaling on dendritic cells (DCs) maturation for antitumor immune response under immunogenic chemotherapy oxaliplatin (OXP) treatment. Defective TLR1 on DCs impaired its maturation ability by HMGB1 and reduced the secretion of IFN from T cells to eradicate the residual tumor cells in vitro. Moreover, systemic inhibition of TLR1/2 dramatically reduced the tumor-infiltrating immune cells by OXP treatment, leading to poor therapeutic response to OXP. On the contrary, administration with TLR1/2 agonist synergistically increased the benefit of OXP treatment and triggered high density of tumor-infiltrating immune cells. We also observed that less tumor-infiltrating cytotoxic T lymphocyte was located within tumor microenvironment in patients bearing TLR1-N248S polymorphism. Taken together, these results showed that patients bearing TLR1-N248S polymorphism might reduce the therapeutic response to adjuvant chemotherapy by attenuating antitumor immune response via impairing HMGB1-mediated DC maturation in locally advanced colon carcinoma patients.

The number of electrophysiology (EP) procedures being performed has dramatically increased in recent years. This escalation necessitates a full understanding by the general anesthesiologist as to the risks, specific considerations, and comorbidities that accompany these now common procedures. Procedures reviewed in this article include atrial fibrillation and flutter ablation, supraventricular tachycardia ablation, ventricular tachycardia ablation, electrical cardioversion, pacemaker insertion, implantable cardioverter-defibrillator (ICD) insertion, and ICD lead extraction. General anesthetic considerations as well as procedure-specific concerns are discussed. Knowledge of these procedures will add to the anesthesiologist's armamentarium in safely caring for patients in the EP laboratory.

The process of matching skeletal muscle blood flow to metabolism is complex and multi-factorial. In response to exercise, increases in cardiac output, perfusion pressure and local vasodilation facilitate an intensity-dependent increase in muscle blood flow. Concomitantly, sympathetic nerve activity directed to both exercising and non-active muscles increases as a function of exercise intensity. Several studies have reported the presence of tonic sympathetic vasoconstriction in the vasculature of exercising muscle at the onset of exercise that persists through prolonged exercise bouts, though it is blunted in an exercise-intensity dependent manner (functional sympatholysis). The collective evidence has resulted in the current dogma that vasoactive molecules released from skeletal muscle, the vascular endothelium, and possibly red blood cells produce local vasodilation, while sympathetic vasoconstriction restrains vasodilation to direct blood flow to the most metabolically active muscles/fibers. Vascular smooth muscle is assumed to integrate a host of vasoactive signals resulting in a precise matching of muscle blood flow to metabolism. Unfortunately, a critical review of the available literature reveals that published studies have largely focused on bulk blood flow and existing experimental approaches with limited ability to reveal the matching of perfusion with metabolism, particularly between and within muscles. This paper will review our current understanding of the regulation of sympathetic vasoconstriction in contracting skeletal muscle and highlight areas where further investigation is necessary.

Cystic fibrosis (CF)-associated liver disease commonly manifests as portal hypertension and its complications. We investigated the proposal that the pathophysiology is of non-cirrhotic rather than cirrhotic portal hypertension. This distinction may have important implications for treatment.We compared liver transplant explants from cystic fibrosis patients with explants from patients with classical cholestatic diseases, primary biliary cholangitis and primary sclerosing cholangitis. Presence of cirrhosis, fibrosis, nodular regenerative hyperplasia, biliary and portal venous pathology were recorded. Quantitation of portal venules in representative section was performed.Nine patients with cystic fibrosis liver disease, 7 primary biliary cholangitis (PBC) and 7 primary sclerosing cholangitis (PSC) were evaluated. Cirrhosis was present in 0/9 of CF patients and 11/14 of the PBC and PSC controls (p 0.01). Nodular regenerative hyperplasia was present in 8/9 of the CF patients but none of the controls (p 0.01). Portal venule numbers per 15 mmThis study demonstrates that non-cirrhotic portal hypertension or obliterative portal venopathy is the predominant hepatic pathophysiology in adult CF patients requiring liver transplantation. It suggests that treatments directed at the hepatic portal venous system may be more effective than current treatment directed at the biliary system in cystic fibrosis.

Dual use of conventional cigarettes and electronic cigarettes presents an emerging public health issue. Previous research has demonstrated a negative relationship between health literacy and conventional cigarette (CIG) use. However, the relationship between health literacy and e-cigarette (ECIG) use remains unclear. This studies examines the possible association of health literacy and CIG, ECIG, or dual use. A multinomial regression was used to model the association between health literacy and current CIG use, current ECIG use, or dual tobacco use status using state-optional data from the 2016 Behavioral Risk Factor Surveillance System (BRFSS; N = 40,404). One-third of the sample (N = 13,478; 33.3%) had initiated tobacco use. Approximately 36.6% of participants exclusively used cigarettes. A smaller proportion of participants were dual users of ECIG and CIGs (7.0%) and e-cigarette exclusive users (4.5%). After adjusting for covariates, higher levels of oral health literacy was associated with lower odds of current dual use. However, there was no significant association between written HL and either conventional cigarette use or electronic cigarette use or after adjusting for covariates. Oral messaging around the dangers of CIG use may be effective at lowering odds of CIG or dual use, especially for those with higher levels of HL. Further research is needed to examine how to best disseminate information regarding the health risks of ECIGs.

Gene-environment interactions (GxE) play a central role in the theoretical relationship between genetic factors and complex traits. While genome wide GxE studies of human behaviors remain underutilized, in part due to methodological limitations, existing GxE research in model organisms emphasizes the importance of interpreting genetic associations within environmental contexts. In this paper, we present a framework for conducting an analysis of GxE using raw data from genome wide association studies (GWAS) and applying the techniques to analyze gene-by-age interactions for alcohol use frequency. To illustrate the effectiveness of this procedure, we calculate genetic marginal effects from a GxE GWAS analysis for an ordinal measure of alcohol use frequency from the UK Biobank dataset, treating the respondent's age as the continuous moderating environment. The genetic marginal effects clarify the interpretation of the GxE associations and provide a direct and clear understanding of how the genetic associations vary across age (the environment). To highlight the advantages of our proposed methods for presenting GxE GWAS results, we compare the interpretation of marginal genetic effects with an interpretation that focuses narrowly on the significance of the interaction coefficients. The results imply that the genetic associations with alcohol use frequency vary considerably across ages, a conclusion that may not be obvious from the raw regression or interaction coefficients. GxE GWAS is less powerful than the standard "main effect" GWAS approach, and therefore require larger samples to detect significant moderated associations. Fortunately, the necessary sample sizes for a successful application of GxE GWAS can rely on the existing and on-going development of consortia and large-scale population-based studies.

Immunosurveillance and immunoscavenging prompted by preoperative chemoradiotherapy (CCRT) may contribute to improve local control and increase survival outcomes for patients with locally advanced rectal cancer (LARC). In this study, we investigated several genotypes of pattern recognition receptors (PRRs) and their impact on therapeutic efficacy in LARC patients treated with CCRT. We found that homozygosis of formyl peptide receptor 1 (FPR1) (E346A/rs867228) was associated with reduced 5-year overall survival (OS) by Kaplan–Meier analysis (62% vs. 81%, p = 0.014) and multivariate analysis [hazard ratio (HR) = 3.383, 95% CI = 1.374–10.239, p = 0.007]. Moreover, in an animal model, we discovered that the FPR1 antagonist, Boc-MLF (Boc-1), reduced CCRT therapeutic efficacy and decreased cytotoxic T cells and T effector memory cells after chemoradiotherapy treatment. Pharmacologic inhibition of FPR1 by Boc-1 decreased T lymphocyte migration to irradiated tumor cells. Therefore, these results revealed that the FPR1 genotype participates in CCRT-elicited anticancer immunity by reducing T lymphocytes migration and infiltration, and that the FPR1-E346A CC genotype can be considered an independent biomarker for chemo- and radiotherapy outcomes.

Background: To our knowledge, there have been no systematic reviews of health economic evaluations of proton therapy specific to lung cancer. Methods: We conducted this systematic review according to the predefined protocol [PROSPERO CRD42022365869]. We summarized the results of the included studies via structured narrative synthesis. Results: We identified four studies (all used passively scattered proton therapy) from 787 searches. Two cost analyses reported that proton therapy was more costly than photon therapy for early- or locally advanced-stage non-small cell lung cancer, one cost-utility analysis reported that proton therapy was dominated by nonproton therapy in early-stage non-small cell lung cancer, and one cost-utility analysis reported that proton therapy was not cost-effective (vs. photon) in locally advanced non-small cell lung cancer. Conclusions: Passively scattered proton therapy was more costly and not cost-effective than photon therapy for early- and locally advanced-stage non-small cell lung cancer. Further health economic evaluations regarding modern proton therapy (such as scanning beam) for common radiotherapy indications of lung cancer are eagerly awaited.

Colorectal cancer (CRC) is the leading cause of cancer-related mortality worldwide. Although the role of tumor programmed cell death 1 ligand 1 (PD-L1) in suppressing antitumor immunity has been validated in various malignances, the impact of PD-L2 (PD-L2/PDCD1LG2) within tumors remains elusive. Here, we examined tumor PD-L2 expression by immunohistochemical analysis and assessed its association with clinicopathological characteristics and the infiltration of intratumoral T lymphocytes in colon carcinoma patients (n = 1264). We found that tumor PD-L2 status was correlated with perineural invasion (PNI) and associated with survival outcome in colon carcinoma patients. The level of tumor PD-L2 was positively associated with tumor PD-L1 expression but inversely associated with the density of CD8+ tumor-infiltrating lymphocytes (TILs). Patients with elevated tumor PD-L2 levels had a favorable 5-year overall survival (OS) compared to patients with low PD-L2 levels (57% vs 40%, p p p = 0.001]. Moreover, tumor PD-L2 expression was inversely associated with the lymphocytic reaction in advanced stage colon carcinoma, suggesting that PD-L2 may be upregulated by a compensatory mechanism to inhibit T cell-mediated anticancer immunity. Taken together, these results show that tumor PD-L2 expression may be an independent prognostic factor for survival outcome in patients with advanced stage colon carcinoma.

Depressive symptoms in parents and caregivers to children are associated with adverse biopsychosocial outcomes for caregivers themselves and the children in their custody. Higher overall and parenting-related stress, including stress over children's unsupervised after-school time, is associated with increased caregiver depression risk. Child after-school program participation is a form of social support that may mitigate parenting-related stress and reduce caregiver depression risk. This study tested for the association between child after-school program participation and caregiver depression in a sample of 486 caregivers in Richmond, Virginia. Child after-school program participation was associated with a significant reduction in the likelihood of a past caregiver depression diagnosis (OR = 0.58, 95% CI = 0.39 - 0.86, p = 0.007). This relationship remained significant after adjusting for the influence of caregiver anxiety, stress, financial hardship, and sociodemographic characteristics (OR = 0.49, 95% CI = 0.27 - 0.86, p = 0.015). Child after-school program participation may function as a protective factor that reduces caregiver depression risk. More research is needed to determine whether the observed association is causal in nature and dosage dependent. Findings from this and future studies may be used to inform evaluation of the impact of after-school programs at the family-level.

INTRODUCTION Adults with obesity are at an increased risk of incident hypertension. Regular aerobic exercise is recommended for the prevention and treatment of hypertension, but whether young adults with obesity exhibit impaired postexercise blood pressure (BP) and vascular responses remains unclear. PURPOSE We tested the hypothesis that young adults with obesity exhibit attenuated postexercise hypotension (PEH) and postexercise peripheral vasodilation compared with young adults without obesity. METHODS Thirty-six normotensive adults without and with obesity (11 men and 7 women per group) underwent measurements of brachial and central BP, and leg blood flow (Doppler ultrasound) at baseline and at 30, 60, and 90 min after acute 1-h moderate-intensity cycling. Leg vascular conductance (LVC) was calculated as flow/mean arterial pressure. RESULTS Both groups exhibited similar brachial and central PEH (peak change from baseline, -2 and -4 mm Hg for brachial and central systolic BPs, respectively, for both groups; time effect, P < 0.05). Both groups also exhibited postexercise peripheral vasodilation, assessed via LVC (time effect, P < 0.05), but its overall magnitude was smaller in young adults with obesity (LVC change from baseline, +47% ± 37%, +29% ± 36%, and +20% ± 29%) compared with young adults without obesity (LVC change from baseline, +88% ± 58%, +59% ± 54%, and +42% ± 51%; group effect, P < 0.05). CONCLUSIONS Although obesity did not impair PEH after acute moderate-intensity exercise, young adults with obesity exhibited smaller postexercise peripheral vasodilation compared with young adults without obesity. Collectively, these findings have identified evidence for obesity-induced alterations in the peripheral vasculature after exercise.

Rationale: Brain metastasis in patients with lung cancer is life-threatening. However, the molecular mechanism for this catastrophic disease remains elusive, and few druggable targets are available. Therefore, this study aimed to identify and characterize proteins that could be used as therapeutic targets. Methods: Proteomic analyses were conducted to identify differentially expressed membrane proteins between brain metastatic lung cancer cells and primary lung cancer cells. A neuronal growth-associated protein, brain acid soluble protein 1 (BASP1), was chosen for further investigation. The clinical relevance of BASP1 in lung adenocarcinoma was first assessed. Tyrosine kinase activity assays and in vitro and in vivo functional assays were conducted to explore the oncogenic mechanisms of BASP1. Results: The protein levels of BASP1 were positively associated with tumor progression and poor prognosis in patients with lung adenocarcinoma. Membrane-bound BASP1 increased EGFR signaling and stabilized EGFR proteins by facilitating their escape from the ubiquitin-proteasome pathway. Reciprocally, activation of EGFR recruited more BASP1 to the plasma membrane, generating a positive feedback loop between BASP1 and EGFR. Moreover, the synergistic therapeutic effects of EGFR tyrosine kinase inhibitor and arsenic trioxide led to a reduction in the level of BASP1 protein observed in lung cancer cells with acquired resistance to EGFR inhibitors. Conclusions: The reciprocal interaction between BASP1 and EGFR facilitates EGFR signaling in brain metastatic lung cancer. Targeting the newly identified BASP1-EGFR interaction could open new venues for lung cancer treatment.

Data for this study were obtained from reproductive-aged women (age 18 to 44 years, at wave 1) from waves 1 (2013–2014) and 2 (2014–2015) of the Population Assessment of Tobacco and Health Study (n = 13,241). Bivariate and multinomial regression analyses were performed associating past 30-day use of cigarettes only, e-cigarettes only, and dual use with perceptions of harm, exposure to tobacco product use, and sociodemographic variables. Cross-sectional and longitudinal analyses were conducted. Of all reproductive-aged women included in the analyses, 75.5% reported no tobacco use, 16.9% reported cigarette use only, 1.5% reported e-cigarette use only, and 6.1% reported dual use within the past 30 days. Perceived harm, tobacco exposure, pregnancy status, age, race/ethnicity, income, education, and sexual orientation were associated with past 30-day use, cross-sectionally at wave 1. Similar associations were found for longitudinal analyses using wave 2 data, except for income and education, which were no longer associated. Results of this study contribute to knowledge regarding prevalence and correlates of tobacco use across exclusive cigarette, exclusive e-cigarette, and dual use among reproductive-aged women.

The effectiveness of opiate treatment programs (OTPs) can be significantly influenced by co-occurring substance use, yet there are no standardized guidelines for assessing the influence of co-occurring substance use on treatment outcomes. In this review, we aim to provide an overview on the status of the assessment of co-occurring substance use during participation in OTPs in the United States. We searched 4 databases—MEDLINE/PubMed, EMBASE, PsychINFO, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL)—from database inception to November 2018 to select relevant publications on OTPs that assessed participants’ co-occurring substance use. We used a standardized protocol to extract study, intervention, and co-occurring substance use characteristics. Methodological quality was assessed using the Quality in Prognosis Studies tool. Of the 3,219 titles screened, 614 abstracts and 191 full-text original publications were assessed, leaving 85 eligible articles. Co-occurring substance use was most often assessed during opioid treatments using combined (pharmacological and behavioral) (n = 57 studies) and pharmacological (n = 25 studies) interventions. Cocaine, alcohol, marijuana, and benzodiazepines were frequently measured, while amphetamines and tobacco were rarely assessed. Great variation existed between studies in the timing and measurement of co-occurring substance use, as well as definitions for substances and polysubstance/polydrug use. Inconsistencies in the investigation of co-occurring substance use make comparison of results across studies challenging. Standardized measures and consensus on research on co-occurring substance use is needed to produce the evidence required to develop personalized treatment programs for persons using multiple substances and to inform best-practice guidelines for addressing polydrug use during participation in OTPs.

This systematic review describes the influence of co-occurring substance use on the effectiveness of opiate treatment programs. MEDLINE/PubMed, Embase, PsychINFO, and the Cumulative Index to Nursing and Allied Health Literature were searched from database inception to November 28, 2018, to identify eligible opioid treatment studies in the United States that assessed the relationship between co-occurring substance use and treatment outcome (i.e., opioid abstinence and treatment retention). A total of 34 eligible studies were included. Overall, co-occurring substance use was associated with negative treatment outcomes regardless of intervention type. However, patterns varied by substance and intervention type. In particular, co-occurring use of cocaine or marijuana with opioids was associated with reduced treatment retention and opioid abstinence regardless of intervention type. Co-occurring use of amphetamines, compared with no use or reduced use of amphetamines, decreased treatment retention. Co-occurring use of alcohol was both positively and negatively associated with treatment outcomes. One study reported a significant positive association between sedative use and opioid abstinence. Generally, findings suggest that combined interventions reported better health outcomes compared with pharmacological or behavioral intervention studies alone. The findings of this review emphasize the need to comprehensively study and address co-occurring substance use to improve opiate treatment programs.

Radiotherapy (RT) mainly elicits antitumor immunity via the cGAS/STING axis for type I interferon (IFN) production. However, dysregulation of cGAS/STING constrains radiotherapy-induced antitumor immunity and type I IFN-dependent cell death and is associated with shorter survival of patients with colorectal cancer (CRC). Due to their tumor tropism, mesenchymal stem cells (MSCs) have shown the potential to deliver therapeutic genes for cancer therapy. Here, we showed that MSCs enhance the sensitivity to RT by inducing TRAIL-dependent cell death and remodel the tumor microenvironment by recruiting CD8+ immune cells to upregulate PD-L1 in the tumor. By engineering MSCs to express CRC-specific soluble TRAIL via adenovirus-associated virus 2 (AAV2), we found that the therapeutic activity of MSC-sTRAIL was superior to that of MSCs alone when combined with RT. Combined treatment with MSC-sTRAIL and RT significantly reduced cell viability and increased apoptosis by inducing TRAIL-dependent cell death in STING-deficient colorectal cancer cells. MSC-sTRAIL directly triggered TRAIL-dependent cell death to overcome the deficiency of the cGAS/STING axis. Moreover, these combination treatments of MSC-sTRAIL and RT significantly remodeled the tumor microenvironment, which was more suitable for anti-PD-L1 immunotherapy. Taken together, this therapeutic strategy represents a novel targeted treatment option for patients with colorectal cancer, especially cGAS/STING-deficient patients.

Locally advanced rectal cancer (LARC) patients are often treated with neoadjuvant long course chemoradiotherapy (NLCCRT) using 45-50.4 Gy conventional fractionated radiotherapy (CFRT). The role of radiotherapy dose escalation is unclear.We identified LARC patients diagnosed from 2011 to 2016 and treated with NLCCRT using CFRT at high dose (54-60 Gy) or standard dose (45-50.4 Gy). In the primary analyses, we used propensity score (PS) weighting to balance the observable potential confounders. The hazard ratio (HR) of death and other endpoints were compared. We also evaluated these outcomes in supplementary analyses via an alternative approach.Our primary analysis included 459 patients. The HR of death when high dose was compared with standard dose was 0.62 (p=0.51). There were also no statistically significant differences in other endpoints or in the supplementary analyses.Overall, survival of LARC patients treated with NLCCT in CFRT was not significantly different between high or standard dose.

Dual use of conventional cigarettes and electronic cigarettes presents an emerging public health issue. Previous research has demonstrated a negative relationship between health literacy and conventional cigarette (CIG) use. However, the relationship between health literacy and e-cigarette (ECIG) use remains unclear. This studies examines the possible association of health literacy and CIG, ECIG, or dual use. A multinomial regression was used to model the association between health literacy and current CIG use, current ECIG use, or dual tobacco use status using state-optional data from the 2016 Behavioral Risk Factor Surveillance System (BRFSS; N = 40,404). One-third of the sample (N = 13,478; 33.3%) had initiated tobacco use. Approximately 36.6% of participants exclusively used cigarettes. A smaller proportion of participants were dual users of ECIG and CIGs (7.0%) and e-cigarette exclusive users (4.5%). After adjusting for covariates, higher levels of oral health literacy was associated with lower odds of current dual use. However, there was no significant association between written HL and either conventional cigarette use or electronic cigarette use or after adjusting for covariates. Oral messaging around the dangers of CIG use may be effective at lowering odds of CIG or dual use, especially for those with higher levels of HL. Further research is needed to examine how to best disseminate information regarding the health risks of ECIGs.

OBJECTIVE This study aims to determine whether current tobacco and/or alcohol use is associated with setting preferences for seeking support for substance use (SU) and mental health (MH) services to African Americans ages 50 and older. METHODS Data from 368 African American individuals (aged 50+) who participated in a community-based needs assessment survey were used. Preferences included community-based (e.g., health centers) and traditional settings (e.g., doctor's office). SU was measured as a categorical variable detailing past-month use of conventional cigarettes and alcohol graded by risk levels. Logistic regression models tested the associations between SU and setting preference before and after adjusting for the influence of self-reported MH diagnoses. RESULTS Prior to adjustment for the influence of MH outcomes, high-risk use of tobacco and alcohol in the past month was associated with a lower odds of preferring MH/SU support in traditional settings (OR = 0.23, 95% CI = 0.06-0.85) compared to participants engaged in no-/low- risk substance use. This association was no longer significant after accounting for the influence of mental health symptoms and covariates. DISCUSSION These results provide preliminary evidence that mental health outcomes mediate the association between substance use and setting preference for seeking MH/SU support in traditional settings. TRANSLATIONAL SIGNIFICANCE This exploratory study encourages additional investigation of the association between substance use, setting preferences, and the likelihood of seeking treatment in community health centers using larger sample sizes. Additional opportunities to offer mental health/substance use support to African American older adults within clinical settings should be explored.

To assess the safety and effectiveness of Schlemm canal stenting for reducing intraocular pressure (IOP) in combination with cataract surgery in the United States cohort of the HORIZON study.Twenty-six clinical sites in the U.S.Prospective clinical trial.Eyes with mild to moderate primary open-angle glaucoma (POAG) on 1 to 4 medications, significant cataract, and an unmedicated diurnal IOP between 22 mm Hg and 34 mm Hg after medication washout were randomized 2:1 to receive the Hydrus microstent or no further treatment after successful cataract surgery. Patients were followed for 24 months. Medication washout and diurnal IOP measurements were repeated at 12 months and 24 months.Two hundred nineteen eyes were randomized to microstent implantation and 112 patients to phacoemulsification only. At 24 months, the diurnal IOP was reduced by 20.0% or more in a greater proportion of eyes in the microstent group (78.5% versus 54.5%; P .001). The mean change in the number of medications was -1.2 ± 0.9 (SD) in the microstent group and -0.8 ± 1.1 in the phaco-only group (P .001), and 78.5% of eyes and 39.2% of eyes, respectively, were medication free (difference 38.8%; P .001).Implantation of a Schlemm canal microstent after phacoemulsification significantly reduced diurnal IOP and medication use compared with phacoemulsification only in patients with mild to moderately severe POAG. The combination procedure was equivalent to cataract surgery alone in terms of visual acuity outcomes and the rate of adverse ocular events.

International audience; Recent research suggests that major meteorite impact events into a Late Hesperian/Early Amazonian ocean likely produced a mega‐tsunami that would have resurfaced coastal areas in northwestern Arabia Terra. The orientations of the associated lobate deposits, a conspicuous type of landforms called Thumbprint Terrain, suggests that if an impact event triggered the mega‐tsunami, the most likely location of the source crater is within the northern plains regions situated north of Arabia Terra. This study focuses on the identification of impact craters that impacted into the ocean and are likely to have produced the tsunami. We selected 10 complex impact craters, based on their diameters, location, and geomorphic characteristics. Of those, the Late Hesperian ~120‐km‐diameter Lomonosov crater exhibits a unique topographic plan view asymmetry (compared to other similar‐sized and similar‐aged craters in the northern plains such as Micoud, Korolev, and Milankovic). We attribute its broad and shallow rim, in part, to an impact into a shallow ocean as well as its subsequent erosion from the collapsing transient water cavity. The likely marine formation of the Lomonosov crater, and the apparent agreement in its age with that of the Thumbprint Terrain unit (~3 Ga), strongly suggests that it was the source crater of the tsunami. These results have implications for the stability of a late northern ocean on Mars.

Evidence indicates that participation in a biobusiness consulting experience has an important impact on the career path of participants while not affecting their scientific productivity.

Niemann-Pick disease, type C1 (NPC1) is an inborn error of metabolism that results in endolysosomal accumulation of unesterified cholesterol. Clinically, NPC1 manifests as cholestatic liver disease in the newborn or as a progressive neurogenerative condition characterized by cerebellar ataxia and cognitive decline. Currently there are no FDA approved therapies for NPC1. Thus, understanding the pathological processes that contribute to neurodegeneration will be important in both developing and testing potential therapeutic interventions. Neuroinflammation and necroptosis contribute to the NPC1 pathological cascade. Receptor Interacting Protein Kinase 1 and 3 (RIPK1 and RIPK3), are protein kinases that play a central role in mediating neuronal necroptosis. Our prior work suggested that pharmacological inhibition of RIPK1 had a significant but modest beneficial effect; however, the inhibitors used in that study had suboptimal pharmacokinetic properties. In this work we evaluated both pharmacological and genetic inhibition of RIPK1 kinase activity. Lifespan in both Npc1(−/−)mice treated with GSK’547, a RIPK1 inhibitor with better pharmacokinetic properties, and Npc1(−/−) :Ripk1(kd/kd) double mutant mice was significantly increased. In both cases the increase in lifespan was modest, suggesting that the therapeutic potential of RIPK1 inhibition, as a monotherapy, is limited. We thus investigated the potential of combining RIPK1 inhibition with 2-hydroxypropyl-β-cyclodextrin (HPβCD) therapy HPβCD has been shown to slow neurological disease progression in NPC1 mice, cats and patients. HPpβCD appeared to have an additive positive effect on the pathology and survival of Npc1(−/−):Ripk1(kd/kd) mice. RIPK1 and RIPK3 are both critical components of the necrosome, thus we were surprised to observe no increase survival in Npc1(−/−);Ripk3(−/−) mice compared to Npc1(−/−) mice. These data suggest that although necroptosis is occurring in NPC1, the observed effects of RIPK1 inhibition may be related to its RIPK3-independent role in neuroinflammation and cytokine production.

Formyl peptide receptor 1 (FPR1) plays a key regulatory role in innate and adaptive immunity. Recently, we reported that the CC genotype of FPR1-E346A (rs867228, c. 1037 A > C) is an independent biomarker for patients with locally advanced rectal cancer (LARC) who received preoperative concurrent chemoradiotherapy (CCRT). Pharmacologic inhibition of FPR1 decreased the migration and infiltration of T lymphocytes into tumor microenvironment after CCRT.

Mars Polar Science is an integrated, compelling system that serves as a nearby analogue to numerous other planets, supports human exploration, and habitability. Mars possesses the closest and most easily accessible layered ice deposits outside of Earth, and accessing those layers to read the climate record would be a triumph for planetary science.

Simple Summary This study aims to evaluate the induction of immunogenic cell death (ICD) for anticancer immunity by the novel topoisomerase I inhibitor lipotecan. These results show that lipotecan can remarkably elicit ICD and increase tumor immunogenicity, which promotes the therapeutic efficacy of radiotherapy compared to conventional chemoradiotherapy in vivo. These results provide potential therapeutic strategies to improve the efficacy of chemoradiotherapy in colorectal cancer (CRC), which may increase the local control rate and decrease tumor relapse in locally advanced rectal cancer (LARC) patients who receive preoperative chemoradiotherapy. Abstract Rectal cancer accounts for 30–40% of colorectal cancer (CRC) and is the most common cancer-related death worldwide. The preoperative neoadjuvant chemoradiotherapy (neoCRT) regimen is the main therapeutic strategy for patients with locally advanced rectal cancer (LARC) to control tumor growth and reduce distant metastasis. However, 30–40% of patients achieve a partial response to neoCRT and suffer from unnecessary drug toxicity side effects and a risk of distant metastasis. In our study, we found that the novel topoisomerase I inhibitor lipotecan (TLC388) can elicit immunogenic cell death (ICD) to release damage-associated molecular patterns (DAMPs), including HMGB1, ANXA1, and CRT exposure. Lipotecan thereby increases cancer immunogenicity and triggers an antitumor immune response to attract immune cell infiltration within the tumor microenvironment (TME) in vitro and in vivo. Taken together, these results show that lipotecan can remodel the tumor microenvironment to provoke anticancer immune responses, which can provide potential clinical benefits to the therapeutic efficacy of neoCRT in LARC patients.

Radiotherapy can boost the therapeutic response to immune checkpoint inhibitors (ICIs) by recruiting T lymphocytes and upregulating PD-L1 expression within the tumor microenvironment (TME). However, in some cases, tumor PD-L1 expression cannot be induced, even in the presence of abundant T lymphocytes, in locally advanced colorectal cancer patients who receive preoperative neoadjuvant concurrent chemoradiotherapy (CCRT). In this study, we found that PD-L1 promoter methylation is negatively correlated with tumor PD-L1 expression and is an independent biomarker for locally advanced colorectal cancer patients. PD-L1 methylation (mCD274) was significantly associated with shorter disease-free survival (cg15837913 loci, p = .0124). By multivariate Cox proportional hazards analyses including influent factors, mCD274 was classified as an independent prognostic factor for poor 5-year DFS [cg15837913, hazard ratio: HR = 4.06, 95% CI = 1.407–11.716, p = .01]. We found that the immunomodulatory agent DNA methyltransferase inhibitor (DNMTi) led to demethylation of the PD-L1 promoter and increased radiotherapy-induced PD-L1 upregulation via interferon β (IFNβ). DNMTi not only induced tumor PD-L1 expression but increased the expression of immune-related genes as well as intratumoral T cell infiltration in vivo. Furthermore, DNMTi strongly enhanced the response to combined treatment with radiotherapy and anti-PD-L1 inhibitors, and prolonged survival in microsatellite stability (MSS) colorectal model. Therefore, DNMTi remodeled the tumor microenvironment to improve the effect of radiotherapy and anti-PD-L1 immunotherapy by directly triggering tumor PD-L1 expression and eliciting stronger immune responses, which may provide potential clinical benefits to colorectal cancer patients in the future.

Obesity is a significant health problem in South Africa. Surgery is the most effective means of durable weight loss for the morbidly obese. Of the surgical options, laparoscopic adjustable gastric banding is the most controversial. We aimed to assess a single surgeon's experience with a specific band.A retrospective observational study of a continuous cohort of laparoscopic adjustable gastric Cousin BioringOutcomes were assessed in 343 patients (4 patients lost to follow-up). The mean follow-up was 39 months (IQR 29-66 months). The mean preoperative BMI was 43.3 kg/mBioring

Rationale: Lung adenocarcinoma (LUAD) is an aggressive disease with high propensity of metastasis. Among patients with early-stage disease, more than 30% of them may relapse or develop metastasis. There is an unmet medical need to stratify patients with early-stage LUAD according to their risk of relapse/metastasis to guide preventive or therapeutic approaches. In this study, we identified 4 genes that can serve both therapeutic and diagnostic (theranostic) purposes. Methods: Three independent datasets (GEO, TCGA, and KMPlotter) were used to evaluate gene expression profile of patients with LUAD by unbiased screening approach. Upon significant genes uncovered, functional enrichment analysis was carried out. The predictive power of their expression on patient prognosis were evaluated. Once confirmed their theranostic roles by integrated bioinformatics, we further conducted in vitro and in vivo validation. Results: We found that four genes (ADAM9, MTHFD2, RRM2, and SLC2A1) were associated with poor patient outcomes with an increased hazard ratio in LUAD. Knockdown of them, both separately and simultaneously, suppressed lung cancer cell proliferation and migration ability in vitro and prolonged survival time in metastatic tumor mouse models. Moreover, these four biomarkers were found to be overexpressed in tumor tissues from LUAD patients, and the total immunohistochemical staining scores correlated with poor prognosis. Conclusions: These results suggest that these four identified genes could be theranostic biomarkers for stratifying high-risk patients who develop relapse/metastasis in early-stage LUAD. Developing therapeutic approaches for the four biomarkers may benefit early-stage LUAD patients after surgery.

Immunosurveillance and immunoscavenging prompted by preoperative chemoradiotherapy (CCRT) may contribute to improve local control and increase survival outcomes for patients with locally advanced rectal cancer (LARC). In this study, we investigated several genotypes of pattern recognition receptors (PRRs) and their impact on therapeutic efficacy in LARC patients treated with CCRT. We found that homozygosis of formyl peptide receptor 1 (FPR1) (E346A/rs867228) was associated with reduced 5-year overall survival (OS) by Kaplan-Meier analysis (62% vs. 81%, p = 0.014) and multivariate analysis [hazard ratio (HR) = 3.383, 95% CI = 1.374-10.239, p = 0.007]. Moreover, in an animal model, we discovered that the FPR1 antagonist, Boc-MLF (Boc-1), reduced CCRT therapeutic efficacy and decreased cytotoxic T cells and T effector memory cells after chemoradiotherapy treatment. Pharmacologic inhibition of FPR1 by Boc-1 decreased T lymphocyte migration to irradiated tumor cells. Therefore, these results revealed that the FPR1 genotype participates in CCRT-elicited anticancer immunity by reducing T lymphocytes migration and infiltration, and that the FPR1-E346A CC genotype can be considered an independent biomarker for chemo- and radiotherapy outcomes.

Programmed cell death-1 (PD-1) has demonstrated impressive clinical outcomes in several malignancies, but its therapeutic efficacy in the majority of colorectal cancers is still low. Therefore, methods to improve its therapeutic efficacy in colorectal cancer (CRC) patients need further investigation. Here, we demonstrate that immunogenic chemotherapeutic agents trigger the induction of tumor PD-L1 expression in vitro and in vivo, a fact which was validated in metastatic CRC patients who received preoperatively neoadjuvant chemotherapy (neoCT) treatment, suggesting that tumor PD-L1 upregulation by chemotherapeutic regimen is more feasible via PD-1/PD-L1 immunotherapy. However, we found that the epigenetic control of tumor PD-L1 via DNA methyltransferase 1 (DNMT1) significantly influenced the response to chemotherapy. We demonstrate that decitabine (DAC) induces DNA hypomethylation, which not only directly enhances tumor PD-L1 expression but also increases the expression of immune-related genes and intratumoral T cell infiltration in vitro and in vivo. DAC was found to profoundly enhance the therapeutic efficacy of PD-L1 immunotherapy to inhibit tumor growth and prolong survival in vivo. Therefore, it can be seen that DAC remodels the tumor microenvironment to improve the effect of PD-L1 immunotherapy by directly triggering tumor PD-L1 expression and eliciting stronger anti-cancer immune responses, providing potential clinical benefits to CRC patients in the future.

Introduction As the use of electronic cigarette (EC) continues to rise in the United States, especially among adolescents and young adults, it is necessary to better understand the factors associated with EC initiation. Specifically, it is unclear how genetic and environmental contributions influence the initiation of EC. Furthermore, the degree to which genetic and environmental influences are shared between EC initiation and conventional cigarette (CC) initiation is unknown. Methods A sample of young adult twins ages 15–20 (N = 858 individuals; 421 complete twin pairs) was used to estimate the genetic and environmental influences on the liability of initiation unique to EC and CC as well as the degree to which these factors are shared between the two. Approximately 24% of participants initiated the use of EC, 19% initiated the use of CC, and 11% initiated the dual use. Results Combined contributions of additive genetic and shared environmental influences were significant for CC (ACC = 0.19 [95% confidence interval {CI} = 0–0.79], p = 0.57; CCC = 0.42 [95% CI = 0–0.70], p = 0.13) and EC (AEC = 0.25 [95% CI = 0–0.83, p = 0.44; CEC = 0.42 [95% CI = 0–0.73], p = 0.12), whereas unique environmental influences were significant (ECC = 0.39 [95% CI = 0.18–0.57], p < 0.001; EEC = 0.32 [95% CI = 0.14–0.56], p < 0.001). Results also demonstrated a significant overlap of the unique environmental (rE = 0.87, p < 0.001) and familial influences contributing to correlation between the two phenotypes in the bivariate analysis. Conclusions These preliminary results suggest that both genes and environmental influences are potential drivers of EC initiation among adolescents and young adults. Implications This article is the first to use a sample of twin to estimate the contributions of genetic and environmental influences toward EC initiation and estimate the potential for overlapping influences with CC initiation. This study has implications for future debate about the etiology of EC and CC use with respect to potential overlapping genetic and environmental influences.

The expression of programmed cell death 1 ligand 1 (PD-L1) and interferon-γ (IFN-γ) is of great interest for the development of chemoradiotherapy and immune checkpoint inhibitor treatments. Patients with nodal metastasis (pN+) tend to have a poor prognosis, even after neoadjuvant chemoradiotherapy (neoCRT) and surgical treatment. In this study, we examined the roles of tumor PD-L1 and IFN-γ before and after neoCRT in locally advanced rectal cancer (LARC) patients. Our results demonstrate that patients with high PD-L1 expression in post-neoCRT tissues exhibit improved 5-year disease-free survival (DFS) and overall survival (OS) compared with those with low PD-L1 expression (p

Programmed cell death-1 (PDCD1/PD-1) and its ligand programmed cell death 1 ligand 1 (CD274/PD-L1) have been reported to suppress anti-tumor T cell-mediated immune responses. However, the clinical significance of CD274 in colorectal cancer were still elusive. We aim to clarify the relationships between CD8+ intratumor-infiltrating lymphocytes (TILs) and CD274 as well as their prognostic values in stage II-III colon carcinoma. Tumor differentiation, perineural invasion (PNI), pN stage and DNA mismatch repair (MMR)-deficient were clearly correlated with CD8+ TILs counts within the tumor microenvironment (p p = 0.02 and p = 0.0195). Tumor CD274 level was significantly correlated with higher CD8+ TILs (p p = 0.14). High tumor CD274 expression [hazard ratio (HR) = 2.16, 95% CI = 1.63–2.86, p p = 0.0007] were associated with improved disease-free survival and overall survival. Additionally, the subgroup of patients who had a high CD8+ TILs/tumor CD274 have better survival outcomes compared with other subgroups (71% vs 53%; p

Physical movement lasting any more than a few seconds (e.g., exercise), requires coordination of motor control with concomitant changes in the cardiovascular and respiratory support necessary to respond to the rapid increases in metabolic demand. Without such coordination, delivery of oxygen and removal of waste products become rate limiting and will restrict the duration, speed, and quality of movement. Fortunately, under healthy conditions, the central and peripheral nervous systems contribute importantly to this remarkable level of coordination via complex mechanisms that remain to be fully elucidated. The purposes of this review are to present the current state of knowledge regarding: (i) mechanisms by which the body maintains appropriate perfusion pressure to all organs during acute bouts of exercise, and (ii) alterations occurring in these mechanisms via central nervous system adaptations when exercise is performed or not performed on a regular basis (e.g., physically active versus sedentary lifestyle, respectively). Results from studies performed in humans and laboratory animals provide the reader a well-rounded knowledge base. They are intended to instill an appreciation of what is known, and not known, about how the brain regulates the cardiovascular system during acute bouts of exercise, and the adaptations that occur when individuals exercise regularly versus when chronically sedentary. Discussion of the latter is intended to provide novel mechanisms for the increased incidence of cardiovascular disease in sedentary individuals versus a reduced incidence in individuals who are regularly active. © 2018 American Physiological Society. Compr Physiol 8:103-151, 2018.

Introduction Concurrent tobacco/alcohol use is common in adults, and associated with the severity of symptoms experienced by those with mental health disorders. However, few studies have explored this relationship across different combinations of tobacco products [i.e., conventional cigarette (CC) and electronic cigarette (EC)] and alcohol. Methods Data from the Wave 1 (2013–2014) Population Assessment of Tobacco and Health study were used. A total of 15,947 adults aged 18 years or older with complete study information were included. Multinomial logistic regression analyses were performed to determine the relationship between lifetime internalizing/externalizing severity and past 30-day use of tobacco and alcohol, adjusting for nicotine dependence (ND), sex, age, race, education, and income. Results Internalizing severity was more strongly associated with CC and alcohol use (moderate AOR = 1.47, 95% CI = 1.22–1.77; high AOR = 1.29, 95% CI = 1.03–1.61) as well as alcohol-exclusive use (moderate AOR = 1.58, 95% CI = 1.27–1.96; high AOR = 1.31, 95% CI = 1.05–1.64) while externalizing severity was more strongly associated with EC and alcohol use (high AOR = 2.97, 95% CI = 1.84–4.81, moderate AOR = 2.29, 95% CI = 1.53–3.43) when accounting for ND compared to none. The relationship between externalizing severity with EC use was dependent on alcohol being used with EC. Conclusions The associations between psychopathology (internalizing vs. externalizing severity) varies by different combinations of alcohol, CC, and EC. Further, these relationships may be mediated through ND. Future investigations into the comorbidity between mental disorder symptoms with tobacco and alcohol use should consider use of specific substances as well as their combination.

Key points Candesartan, an inverse agonist of the type 1 angiotensin II receptor (AT1 R), causes a concentration-dependent inhibition of pressure-dependent myogenic tone consistent with previous reports of mechanosensitivity of this G protein-coupled receptor. Mechanoactivation of the AT1 R occurs independently of local angiotensin II production and the type 2 angiotensin receptor. Mechanoactivation of the AT1 R stimulates actin polymerization by a protein kinase C-dependent mechanism, but independently of a change in intracellular Ca2+ . Using atomic force microscopy, changes in single vascular smooth muscle cell cortical actin are observed to remodel following mechanoactivation of the AT1 R. Abstract The Gq/11 protein-coupled angiotensin II type 1 receptor (AT1 R) has been shown to be activated by mechanical stimuli. In the vascular system, evidence supports the AT1 R being a mechanosensor that contributes to arteriolar myogenic constriction. The aim of this study was to determine if AT1 R mechanoactivation affects myogenic constriction in skeletal muscle arterioles and to determine underlying cellular mechanisms. Using pressure myography to study rat isolated first-order cremaster muscle arterioles the AT1 R inhibitor candesartan (10-7 -10-5 m) showed partial but concentration-dependent inhibition of myogenic reactivity. Inhibition was demonstrated by a rightward shift in the pressure-diameter relationship over the intraluminal pressure range, 30-110 mmHg. Pressure-induced changes in global vascular smooth muscle intracellular Ca2+ (using Fura-2) were similar in the absence or presence of candesartan, indicating that AT1 R-mediated myogenic constriction relies on Ca2+ -independent downstream signalling. The diacylglycerol analogue 1-oleoyl-2-acetyl-sn-glycerol (OAG) reversed the inhibitory effect of candesartan, while this rescue effect was prevented by the protein kinase C (PKC) inhibitor GF 109203X. Both candesartan and PKC inhibition caused increased G-actin levels, as determined by Western blotting of vessel lysates, supporting involvement of cytoskeletal remodelling. At the single vascular smooth muscle cell level, atomic force microscopy showed that cell swelling (stretch) with hypotonic buffer also caused thickening of cortical actin fibres and this was blocked by candesartan. Collectively, the present studies support growing evidence for novel modes of activation of the AT1 R in arterioles and suggest that mechanically activated AT1 R generates diacylglycerol, which in turn activates PKC which induces the actin cytoskeleton reorganization that is required for pressure-induced vasoconstriction.

Radiation therapy is one of the most effective tools for cancer treatment. In recent years, intensity-modulated radiation therapy has become increasingly popular in that target dose-escalation can be done while sparing adjacent normal tissues. For this reason, the development of measures to pave the way for accurate target delineation is of great interest. With the integration of functional information obtained by biological imaging with radiotherapy, strategies using advanced biological imaging to visualize metabolic pathways and to improve therapeutic index and predict treatment response are discussed in this article.

This study aims to evaluate the cost-effectiveness of surgical resection (S) and Cesium-131 (Cs-131) [S + Cs-131] intraoperative brachytherapy versus S and stereotactic radiosurgery (SRS) [S + SRS] for the treatment of brain metastases. Treatment records as well as hospital and outpatient charts of 49 patients with brain metastases between 2008 and 2012 who underwent S + Cs-131 (n = 24) and S + SRS (n = 25) were retrospectively reviewed. Hospital charges were compared for the single treatment in question. Means and curves of survival time were defined by the Kaplan-Meier estimator, with the cost analysis focusing on the time period of the relevant treatment. Quality adjusted life years (QALY) and Incremental cost-effectiveness ratios (ICER) were calculated for each treatment option as a measure of cost-effectiveness. The direct hospital costs of treatments per patient were: S + Cs131 = $19,271 and S + SRS = $44,219. The median survival times of S + Cs-131 and S + SRS were 15.5 and 11.3 months, and the 12 month survival rates were 61 % and 49 % (P = 0.137). The QALY for S + SRS when compared to S + Cs-131 yielded a p

Changing institutional culture to be more diverse and inclusive within the biomedical academic community is difficult for many reasons. Herein we present evidence that a collaborative model involving multiple institutions of higher education can initiate and execute individual institutional change directed at enhancing diversity and inclusion at the postdoctoral researcher (postdoc) and junior faculty level by implementing evidence-based mentoring practices. A higher education consortium, the Big Ten Academic Alliance, invited individual member institutions to send participants to one of two types of annual mentor training: 1) "Mentoring-Up" training for postdocs, a majority of whom were from underrepresented groups; 2) Mentor Facilitator training-a train-the-trainer model-for faculty and senior leadership. From 2016 to 2019, 102 postdocs and 160 senior faculty and administrative leaders participated. Postdocs reported improvements in their mentoring proficiency (87%) and improved relationships with their PIs (71%). 29% of postdoc respondents transitioned to faculty positions, and 85% of these were underrepresented and 75% were female. 59 out of the 120 faculty and administrators (49%) trained in the first three years provided mentor training on their campuses to over 3000 undergraduate and graduate students, postdocs and faculty within the project period. We conclude that early stage biomedical professionals as well as individual institutions of higher education benefited significantly from this collaborative mentee/mentor training model.

Reactivation of T cell immunity by PD-1/PD-L1 immune checkpoint blockade has been shown to be a promising cancer therapeutic strategy. However, PD-L1 immunohistochemical readout is inconsistent with patient response, which presents a clinical challenge to stratify patients. Because PD-L1 is heavily glycosylated, we developed a method to resolve this by removing the glycan moieties from cell surface antigens via enzymatic digestion, a process termed sample deglycosylation. Notably, deglycosylation significantly improves anti-PD-L1 antibody binding affinity and signal intensity, resulting in more accurate PD-L1 quantification and prediction of clinical outcome. This proposed method of PD-L1 antigen retrieval may provide a practical and timely approach to reduce false-negative patient stratification for guiding anti-PD-1/PD-L1 therapy.

Dysfunctional mitochondria have been shown to enhance cancer cell proliferation, reduce apoptosis, and increase chemoresistance. Chemoresistance develops in nearly all patients with colorectal cancer, leading to a decrease in the therapeutic efficacies of anticancer agents. However, the effect of dynamin-related protein 1 (Drp1)-mediated mitochondrial fission on chemoresistance in colorectal cancer is unclear. Here, we found that the release of high-mobility group box 1 protein (HMGB1) in conditioned medium from dying cells by chemotherapeutic drugs and resistant cells, which triggered Drp1 phosphorylation via its receptor for advanced glycation end product (RAGE). RAGE signals ERK1/2 activation to phosphorylate Drp1 at residue S616 triggerring autophagy for chemoresistance and regrowth in the surviving cancer cells. Abolishment of Drp1 phosphorylation by HMGB1 inhibitor and RAGE blocker significantly enhance sensitivity to the chemotherapeutic treatment by suppressing autophagy. Furthermore, patients with high phospho-Drp1Ser616 are associated with high risk on developing tumor relapse, poor 5-year disease-free survival (DFS) and 5-year overall survival (OS) after neoadjuvant chemoradiotherapy (neoCRT) treatment in locally advanced rectal cancer (LARC). Moreover, patients with RAGE-G82S polymorphism (rs2070600) are associated with high phospho-Drp1Ser616 within tumor microenvironment. These findings suggest that the release of HMGB1 from dying cancer cells enhances chemoresistance and regrowth via RAGE-mediated ERK/Drp1 phosphorylation.