Lack of association of genetic variants for diabetic retinopathy in Taiwanese patients with diabetic nephropathy

[[abstract]]Objective Diabetic nephropathy (DN) and diabetic retinopathy (DR) comprise major microvascular complications of diabetes that occur with a high concordance rate in patients and are considered to potentially share pathogeneses. In this case-control study, we sought to investigate whether DR-related single nucleotide polymorphisms (SNPs) exert pleiotropic effects on renal function outcomes among patients with diabetes. Research design and methods A total of 33 DR-related SNPs were identified by replicating published SNPs and via a genome-wide association study. Furthermore, we assessed the cumulative effects by creating a weighted genetic risk score and evaluated the discriminatory and prediction ability of these genetic variants using DN cases according to estimated glomerular filtration rate (eGFR) status along with a cohort with early renal functional decline (ERFD). Results Multivariate logistic regression models revealed that the DR-related SNPs afforded no individual or cumulative genetic effect on the nephropathy risk, eGFR status or ERFD outcome among patients with type two diabetes in Taiwan. Conclusion Our findings indicate that larger studies would be necessary to clearly ascertain the effects of individual genetic variants and further investigation is also required to identify other genetic pathways underlying DN.[[notice]]補正完

Characterizing Acupuncture Stimuli Using Brain Imaging with fMRI - A Systematic Review and Meta-Analysis of the Literature

Background The mechanisms of action underlying acupuncture, including acupuncture point specificity, are not well understood. In the previous decade, an increasing number of studies have applied fMRI to investigate brain response to acupuncture stimulation. Our aim was to provide a systematic overview of acupuncture fMRI research considering the following aspects: 1) differences between verum and sham acupuncture, 2) differences due to various methods of acupuncture manipulation, 3) differences between patients and healthy volunteers, 4) differences between different acupuncture points. Methodology/Principal Findings We systematically searched English, Chinese, Korean and Japanese databases for literature published from the earliest available up until September 2009, without any language restrictions. We included all studies using fMRI to investigate the effect of acupuncture on the human brain (at least one group that received needle-based acupuncture). 779 papers were identified, 149 met the inclusion criteria for the descriptive analysis, and 34 were eligible for the meta-analyses. From a descriptive perspective, multiple studies reported that acupuncture modulates activity within specific brain areas, including somatosensory cortices, limbic system, basal ganglia, brain stem, and cerebellum. Meta-analyses for verum acupuncture stimuli confirmed brain activity within many of the regions mentioned above. Differences between verum and sham acupuncture were noted in brain response in middle cingulate, while some heterogeneity was noted for other regions depending on how such meta-analyses were performed, such as sensorimotor cortices, limbic regions, and cerebellum. Conclusions Brain response to acupuncture stimuli encompasses a broad network of regions consistent with not just somatosensory, but also affective and cognitive processing. While the results were heterogeneous, from a descriptive perspective most studies suggest that acupuncture can modulate the activity within specific brain areas, and the evidence based on meta-analyses confirmed some of these results. More high quality studies with more transparent methodology are needed to improve the consistency amongst different studies

2009

ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o n BCL2 translocations are more frequently found in the GCB subtype, whereas 18q21 locus amplification is more common in the ABC subtype of DLBCL. 3, Design and Methods Patients We studied 327 cases of previously untreated de novo DLBCL, diagnosed between January 2002 and October 2009, and collected as part of the International DLBCL Rituxan-CHOP Consortium Program Study. These cases were analyzed for Bcl-2 protein expression, and BCL2 and MYC gene abnormalities, and gene expression profiling (GEP) was performed. All cases were reviewed by a group of hematopathologists (SMM, MAP, MBM, AT, and KHY), and the diagnoses were confirmed based on World Health Organization classification criteria. Patients with transformation from low grade lymphoma, those with composite follicular lymphoma, primary mediastinal large B-cell lymphoma, primary cutaneous and primary central nervous system DLBCL were excluded from the analysis due to the unique biological features of these types of lymphoma. All patients were adults who were negative for human immunodeficiency virus and had sufficient clinical data and clinical follow-up. Patients in this study were treated with R-CHOP (n=291, 89%) or R-CHOP-like regimens (n=36, 11%; CHOP scheme adopting different anthracyclines i.e. novantrone or epirubicin). All patients with advanced stage disease received six (92%) or eight (8%) cycles, every 21 days, with or without radiotherapy for residual disease or initial bulky disease; localized cases received at least three cycles followed by radiotherapy or six cycles without radiotherapy. The current study was approved by each of the participating centers' Institutional Review Boards, and the overall collaborative study was approved by the Institutional Review Board at The University of Texas MD Anderson Cancer Center in Houston, Texas, USA. Immunohistochemistry for Bcl-2 and cut-off determination Bcl-2 protein expression was evaluated in all patients using a monoclonal anti-Bcl-2 antibody (Clone-124, Dako, Carpinteria, CA, USA) and standard immunohistochemical methods. The formalin-fixed, paraffin-embedded tissue slides underwent deparaffinization and heat-induced antigen retrieval techniques. An endogenous biotin-blocking kit (Ventana) was used to decrease background staining. Following antigen retrieval and primary antibody incubation, the reaction was completed in a Ventana ES instrument using a diaminobenzidine immunoperoxidase detection kit (Ventana). Immunoreactivity was determined without knowledge of the patients' survival, clinical data, or GEP data. The samples were analyzed independently by a group of four hematopathologists/pathologists in addition to the hematopathologist of each of the contributing centers, and disagreements were resolved by joint review at a multi-headed microscope. An average of 300-400 cells in four to five fields were counted in the tissue microarray cores. A percentage of tumor cell staining ≥50% was considered positive after receiver operating characteristic (ROC) curve analysis was implemented to assess the discriminatory accuracy of Bcl-2 protein in recognizing patients with different overall survival (OS) and progression-free survival (PFS). The 50% value was established from the analysis of the area under the ROC curve (AUROC) and had the maximum specificity and sensibility for OS and PFS discrimination in our patients (AUROC=0.564, P=0.017 for OS and AUROC=0.564, P=0.015 for PFS). 31 Gene expression profiling analysis RNA was extracted from 327 formalin-fixed, paraffin-embedded tissue samples using a HighPure Paraffin RNA Extraction Kit (Roche Applied Science). Fifty nanograms of RNA were transcribed into cDNA, linearly amplified using the WT-Ovation™ FFPE System (Nugen), and biotin-labeled using FL-Ovation™ cDNA Biotin Module V2 (Nugen) in all cases. For GeneChip hybridization, 5 μg of WT-Ovation amplified cDNA were applied to HG-U133 Plus 2.0 GeneChips (Affymetrix) and hybridized overnight. GeneChips were washed, stained, and scanned using the Fluidic Station 450 and GeneChip Scanner 3000 (Affymetrix) according to the manufacturer's recommendations. For data analysis and classification, the microarray DQN (trimmed mean of differences of perfect match and mismatch intensities with quantile normalization) signals were generated and normalized to the quantiles of beta distribution with parameters p=1.2 and q=3 as previously described. 32 A Bayesian model was also utilized to determine the class probability. The classification model was built on the 47 paired formalin-fixed, paraffin-embedded tissue sample dataset previously generated with a confidence rate of 90-100% in fresh frozen tissue and 92-100% in formalin-fixed, paraffinembedded tissue. The same methodology developed during this study has been validated and demonstrated to be applicable by using the LLMPP dataset in the Gene Expression Omnibus (GEO) database GSE#10846 that has 181 CHOP-treated and 233 R-CHOP-treated DLBCL patients with fresh-frozen samples. 3, Validation set To validate our observations in predicting survival in an independent series of cases, we analyzed a second group of 120 archival DLBCL cases studied similarly to the first cohort except for MYC analysis that was not available (GCB 49%, ABC 40%, unclassified 11%; BCL2 translocations in 18%; Bcl-2 overexpression in 54%). All these patients had been treated with R-CHOP and the same selection criteria as those for the first cohort were applied. The clinical characteristics at presentation of the patients in the validation set were not significantly different from those of the patients in the test set. Statistical analysis Following pre-defined criteria, 33 PFS was measured from the time of diagnosis to the time of progression or death from any cause. OS was measured from the time of diagnosis to last followup or death from any cause. Only patients with a follow-up of longer than 12 months were included in the survival analysis. The actuarial probabilities of PFS and OS were determined using the Kaplan-Meier method, and differences were compared using the log-rank test. A Cox proportional-hazards model was used for multivariate analysis. The χ 2 test or Mann-Whitney test was applied to assess differences between variables. The interobserver agreement for FISH was assessed using the κ statistic; a κ value of >0.75 implied excellent agreement. All statistical calculations, except for ROC and the κ statistic which were performed with SPSS 18.0 (SPSS Inc., Chicago, IL, USA), were conducted using StatView (Abacus Concepts, Berkeley, CA, USA). Results Patients' characteristics and outcome The median age of the patients at diagnosis was 62 years (range, 18-86). Their clinical characteristics are reported in BCL2 and MYC genes in the subgroups defined by gene expression profiling Sixty patients (18.3%) had DLBCL with BCL2 gene translocations, and 50 (15.3%) had BCL2 gene amplifications. The presence of BCL2 translocations was not associated with any clinical prognostic variable at diagnosis, except for Ann Arbor Stage (70% versus 49% with stage III-IV, P=0.004), as shown in The OS and PFS rates of patients with BCL2 translocations were similar to those of patients without BCL2 translocations, irrespectively of MYC status. When we restricted the analysis to the GCB subtype, patients with BCL2 translocations alone, in the absence of MYC breaks, had a significantly worse outcome than GCB patients without BCL2 translocations (3-year PFS of 53% versus 76%, respectively; P=0.0002). The outcome of patients with BCL2 rearranged GCB subtype was similar to that of the patients with the ABC subtype of DLBCL (52%, P=0.30), but still better than that of the patients with double hit lymphomas (P<0.0001, The presence of MYC breaks alone in the 19 patients without concomitant BCL2 translocations was not associated with impaired PFS (P=0.70) or OS (P=0.66) in the whole cohort, but was associated with inferior OS (P=0.03), but not PFS (P=0.22), in patients with GCB-DLBCL (only 9 with isolated MYC breaks). As shown in BCL2 gains were not prognostic in any of the subgroups of patients. Particular consideration of high-level amplifications was of no additional prognostic value. Bcl-2 protein expression, clinical characteristics, fluorescence in situ hybridization and gene expression profiling None of the common clinical characteristics of our patients at the time of presentation was significantly associated with Bcl-2 protein expression except age, with older patients more often being Bcl-2 positive (≥60 years old, P=0.02). Bcl-2 protein expression in GEP-and FISHdefined subgroups is shown in © F e r r a t a S t o r t i F o u n d a t i o n patients without the BCL2 translocation (range, 0-100%; median 60%). Bcl-2 protein expression was significantly associated with worse PFS (P=0.01) and OS (P=0.02) in the whole cohort, but when patients were divided according to GEPdefined subtypes, we observed that higher Bcl-2 expression was associated with significantly inferior PFS in the GCB subgroup (P=0.04), but not in the ABC subgroup (P=0.57), as shown in Multivariate analysis Multivariate analysis of all 137 patients with the GCB subtype of DLBCL showed that BCL2 translocations (HR 0.40, 95% CI: 0.18-0.89; P=0.02), but not Bcl-2 expression (HR 1.01, 95% CI: 0.45-2.21; P=0.98), MYC breaks (HR 0.25, 95% CI: 0.10-0.59; P=0.001), and IPI score (HR 0.41, 95% CI: 0.20-0.84; P=0.01), were independently associated with patients' outcome. Results were not modified after each molecular feature was computed with age as a continuous parameter. C. Visco et al. 258 haematologica | 2013; 98(2) Overall survival Progression-free survival Four-hundred and forty-four genes were found to be differentially expressed (>1.5 fold and P<0.005) in DLBCL patients with or without BCL2 translocations including both GCB and ABC subtypes. In the GCB group, however, only 43 genes were differentially expressed among patients with and without BCL2 translocations ( Interestingly, a number of genes overexpressed in the BCL2 translocated group are involved in the control of angiogenesis and the inflammatory response (AIMP1, PPIA, and ALOX), while others are involved in promoting apoptosis or regulating B-cell signaling (STK17A, RAL-GPS2, NCOA3, STRBP, and ZNF117). 35-37 C. Visco et al. 260 haematologica | 2013; 98(2) © F e r r a t a S t o r t i F o u n d a t i o n Discussion We addressed the clinical impact of BCL2 aberrations and their relationship to Bcl-2 protein expression in a large series of patients with DLBCL homogeneously treated with R-CHOP, with known MYC gene status and molecularly characterized according to GEP analysis. We were able to establish the role of the BCL2 gene in different subtypes of DLBCL, irrespectively of concomitant MYC aberrations. We found that isolated BCL2 translocations, in the absence of MYC breaks, were associated with a poor outcome in the subset of patients with GCB-DLBCL, and that the prognosis of these patients was similar to that of patients with ABC-DLBCL. The concomitant presence of MYC breaks (double hit lymphoma) further worsened the outcome of these patients. The role of Bcl-2 protein expression appeared dependent on its association with BCL2 translocations, as outlined by multivariate analysis and survival curves As determined by FISH break apart probe analysis, the overall frequency of BCL2 translocations in de novo DLBCL was 18.3%. The BCL2 translocations were almost exclusively associated with GCB-DLBCL, found in 34.5% of cases The impact of BCL2 translocations on survival in our series could not be explained by differences in the clinical features of the patients because there was no association between the presence of BCL2 translocations and IPI risk groups (P=0.90, A C B FIGURE A COLORI SOLO ONLINE © F e r r a t a S t o r t i F o u n d a t i o n with isolated BCL2 or MYC lesions. Confirming previous findings, In this series, Bcl-2 protein was overexpressed in half of the patients with GCB-DLBCL and in 72% of patients with ABC-DLBCL 18,39 However, Bcl-2 overexpression had prognostic value only in the GCB subtype, as already observed by others in the era of R-CHOP therapy. Iqbal et al. 22 Secondly, Bcl-2 protein expression in Iqbal's study was significantly associated with adverse clinical prognostic factors (stage III-IV, elevated lactate dehydrogenase, high IPI risk group) in GCB-DLBCL, which was not the case in our study. Finally, no mention was made about exclusion of possibly confounding DLBCL subtypes such as double hit lymphoma, primary cutaneous or primary central nervous system DLBCL. We also acknowledge that different findings in the literature regarding BCL2 rearrangements or protein expression could very well be related to lack of uniformity between different studies in terms of Bcl-2 staining and scoring. Moreover, patients' characteristics in the different series, differences in the management of the cases as they were not in clinical trials, data collection regarding outcome, and sometimes short follow-up times may also have contributed to different results. Our GEP analysis revealed that patients with BCL2 translocations substantially differed with respect to important recurrent oncogenic events, which may contribute to the adverse outcome of the subgroup of GCB-DLBCL patients with BCL2 translocations. Up-regulation of the BCL11A gene occurred exclusively in the group of patients with BCL2 translocations We confirm that the outcome of GCB-DLBCL patients should be interpreted in the context of abnormalities of the MYC and BCL2 genes. While the MYC rearrangement is quite rare, it is rarely found as the sole genetic abnormality, and its clinical relevance is mainly related to a double hit mechanism, BCL2 rearrangements are present in a considerable fraction of patients with the GCB subtype who have similar outcomes to those of patients with the ABC subtype. Our results confirm that the GCB and ABC subtypes of DLBCL have distinct pathogeneses, and support the rationale for further classification of different subgroups. © F e r r a t a S t o r t i F o u n d a t i o n Funding CV is a hematologist supported by Sa

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: A systematic analysis for the Global Burden of Disease Study 2017

Background: The Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017) includes a comprehensive assessment of incidence, prevalence, and years lived with disability (YLDs) for 354 causes in 195 countries and territories from 1990 to 2017. Previous GBD studies have shown how the decline of mortality rates from 1990 to 2016 has led to an increase in life expectancy, an ageing global population, and an expansion of the non-fatal burden of disease and injury. These studies have also shown how a substantial portion of the world's population experiences non-fatal health loss with considerable heterogeneity among different causes, locations, ages, and sexes. Ongoing objectives of the GBD study include increasing the level of estimation detail, improving analytical strategies, and increasing the amount of high-quality data. Methods: We estimated incidence and prevalence for 354 diseases and injuries and 3484 sequelae. We used an updated and extensive body of literature studies, survey data, surveillance data, inpatient admission records, outpatient visit records, and health insurance claims, and additionally used results from cause of death models to inform estimates using a total of 68 781 data sources. Newly available clinical data from India, Iran, Japan, Jordan, Nepal, China, Brazil, Norway, and Italy were incorporated, as well as updated claims data from the USA and new claims data from Taiwan (province of China) and Singapore. We used DisMod-MR 2.1, a Bayesian meta-regression tool, as the main method of estimation, ensuring consistency between rates of incidence, prevalence, remission, and cause of death for each condition. YLDs were estimated as the product of a prevalence estimate and a disability weight for health states of each mutually exclusive sequela, adjusted for comorbidity. We updated the Socio-demographic Index (SDI), a summary development indicator of income per capita, years of schooling, and total fertility rate. Additionally, we calculated differences between male and female YLDs to identify divergent trends across sexes. GBD 2017 complies with the Guidelines for Accurate and Transparent Health Estimates Reporting. Findings: Globally, for females, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and haemoglobinopathies and haemolytic anaemias in both 1990 and 2017. For males, the causes with the greatest age-standardised prevalence were oral disorders, headache disorders, and tuberculosis including latent tuberculosis infection in both 1990 and 2017. In terms of YLDs, low back pain, headache disorders, and dietary iron deficiency were the leading Level 3 causes of YLD counts in 1990, whereas low back pain, headache disorders, and depressive disorders were the leading causes in 2017 for both sexes combined. All-cause age-standardised YLD rates decreased by 3·9% (95% uncertainty interval [UI] 3·1-4·6) from 1990 to 2017; however, the all-age YLD rate increased by 7·2% (6·0-8·4) while the total sum of global YLDs increased from 562 million (421-723) to 853 million (642-1100). The increases for males and females were similar, with increases in all-age YLD rates of 7·9% (6·6-9·2) for males and 6·5% (5·4-7·7) for females. We found significant differences between males and females in terms of age-standardised prevalence estimates for multiple causes. The causes with the greatest relative differences between sexes in 2017 included substance use disorders (3018 cases [95% UI 2782-3252] per 100 000 in males vs 1400 [1279-1524] per 100 000 in females), transport injuries (3322 [3082-3583] vs 2336 [2154-2535]), and self-harm and interpersonal violence (3265 [2943-3630] vs 5643 [5057-6302]). Interpretation: Global all-cause age-standardised YLD rates have improved only slightly over a period spanning nearly three decades. However, the magnitude of the non-fatal disease burden has expanded globally, with increasing numbers of people who have a wide spectrum of conditions. A subset of conditions has remained globally pervasive since 1990, whereas other conditions have displayed more dynamic trends, with different ages, sexes, and geographies across the globe experiencing varying burdens and trends of health loss. This study emphasises how global improvements in premature mortality for select conditions have led to older populations with complex and potentially expensive diseases, yet also highlights global achievements in certain domains of disease and injury

Global, regional, and national age-sex-specific mortality and life expectancy, 1950-2017: a systematic analysis for the Global Burden of Disease Study 2017

Background: Assessments of age-specific mortality and life expectancy have been done by the UN Population Division, Department of Economics and Social Affairs (UNPOP), the United States Census Bureau, WHO, and as part of previous iterations of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD). Previous iterations of the GBD used population estimates from UNPOP, which were not derived in a way that was internally consistent with the estimates of the numbers of deaths in the GBD. The present iteration of the GBD, GBD 2017, improves on previous assessments and provides timely estimates of the mortality experience of populations globally. Methods: The GBD uses all available data to produce estimates of mortality rates between 1950 and 2017 for 23 age groups, both sexes, and 918 locations, including 195 countries and territories and subnational locations for 16 countries. Data used include vital registration systems, sample registration systems, household surveys (complete birth histories, summary birth histories, sibling histories), censuses (summary birth histories, household deaths), and Demographic Surveillance Sites. In total, this analysis used 8259 data sources. Estimates of the probability of death between birth and the age of 5 years and between ages 15 and 60 years are generated and then input into a model life table system to produce complete life tables for all locations and years. Fatal discontinuities and mortality due to HIV/AIDS are analysed separately and then incorporated into the estimation. We analyse the relationship between age-specific mortality and development status using the Socio-demographic Index, a composite measure based on fertility under the age of 25 years, education, and income. There are four main methodological improvements in GBD 2017 compared with GBD 2016: 622 additional data sources have been incorporated; new estimates of population, generated by the GBD study, are used; statistical methods used in different components of the analysis have been further standardised and improved; and the analysis has been extended backwards in time by two decades to start in 1950. Findings: Globally, 18·7% (95% uncertainty interval 18·4–19·0) of deaths were registered in 1950 and that proportion has been steadily increasing since, with 58·8% (58·2–59·3) of all deaths being registered in 2015. At the global level, between 1950 and 2017, life expectancy increased from 48·1 years (46·5–49·6) to 70·5 years (70·1–70·8) for men and from 52·9 years (51·7–54·0) to 75·6 years (75·3–75·9) for women. Despite this overall progress, there remains substantial variation in life expectancy at birth in 2017, which ranges from 49·1 years (46·5–51·7) for men in the Central African Republic to 87·6 years (86·9–88·1) among women in Singapore. The greatest progress across age groups was for children younger than 5 years; under-5 mortality dropped from 216·0 deaths (196·3–238·1) per 1000 livebirths in 1950 to 38·9 deaths (35·6–42·83) per 1000 livebirths in 2017, with huge reductions across countries. Nevertheless, there were still 5·4 million (5·2–5·6) deaths among children younger than 5 years in the world in 2017. Progress has been less pronounced and more variable for adults, especially for adult males, who had stagnant or increasing mortality rates in several countries. The gap between male and female life expectancy between 1950 and 2017, while relatively stable at the global level, shows distinctive patterns across super-regions and has consistently been the largest in central Europe, eastern Europe, and central Asia, and smallest in south Asia. Performance was also variable across countries and time in observed mortality rates compared with those expected on the basis of development. Interpretation: This analysis of age-sex-specific mortality shows that there are remarkably complex patterns in population mortality across countries. The findings of this study highlight global successes, such as the large decline in under-5 mortality, which reflects significant local, national, and global commitment and investment over several decades. However, they also bring attention to mortality patterns that are a cause for concern, particularly among adult men and, to a lesser extent, women, whose mortality rates have stagnated in many countries over the time period of this study, and in some cases are increasing

Inhibition of iRhom1 by CD44-targeting nanocarrier for improved cancer immunochemotherapy

The multifaceted chemo-immune resistance is the principal barrier to achieving cure in cancer patients. Identifying a target that is critically involved in chemo-immune-resistance represents an attractive strategy to improve cancer treatment. iRhom1 plays a role in cancer cell proliferation and its expression is negatively correlated with immune cell infiltration. Here we show that iRhom1 decreases chemotherapy sensitivity by regulating the MAPK14-HSP27 axis. In addition, iRhom1 inhibits the cytotoxic T-cell response by reducing the stability of ERAP1 protein and the ERAP1-mediated antigen processing and presentation. To facilitate the therapeutic translation of these findings, we develop a biodegradable nanocarrier that is effective in codelivery of iRhom pre-siRNA (pre-siiRhom) and chemotherapeutic drugs. This nanocarrier is effective in tumor targeting and penetration through both enhanced permeability and retention effect and CD44-mediated transcytosis in tumor endothelial cells as well as tumor cells. Inhibition of iRhom1 further facilitates tumor targeting and uptake through inhibition of CD44 cleavage. Co-delivery of pre-siiRhom and a chemotherapy agent leads to enhanced antitumor efficacy and activated tumor immune microenvironment in multiple cancer models in female mice. Targeting iRhom1 together with chemotherapy could represent a strategy to overcome chemo-immune resistance in cancer treatment