Implications for Tumor Microenvironment and Epithelial Crosstalk in the Management of Gastrointestinal Cancers

Rapid advances in technology are revealing previously unknown organization, cooperation, and limitations within the population of nontumor cells surrounding the tumor epithelium known as the tumor microenvironment (TME). Nowhere are these findings more pertinent than in the gastrointestinal (GI) tract where exquisite cell specialization supports a complex microenvironmental niche characterized by rapid stemness-associated cell turnover, pathogen sensing, epithelial orchestration of immune signaling, and other facets that maintain the complex balance between homeostasis, inflammation, and disease. Here, we summarize and discuss select emerging concepts in the precancerous microenvironment, TME, and tumor epithelial-TME crosstalk as well as their implications for the management of GI cancers

Health care provider's experience and perspective of cervical cancer screening in Singapore: A qualitative study

BackgroundIn Singapore, the current cervical cancer screening (CCS) coverage rate of 48% falls below the national target of 70%. Health care providers (HCPs) play a critical role in promoting CCS uptake. However, there is limited understanding of the perspectives of HCPs regarding CCS. Hence, we aimed to understand the challenges encountered by HCPs delivering CCS in different care settings in the Singapore health system. We also aimed to explore perspectives on newer features of CCS such as self-sampling and HPV genotyping.MethodsPhysicians, nurses, program administrators and laboratory technicians involved with CCS were invited for a one-on-one semi-structured interview conducted over Zoom between May to August 2021. The interviews were transcribed and analyzed using thematic analysis.ResultsEighteen HCPs from 12 institutions were interviewed. Most participants were women (61.1%) and worked in public health institutions (72.2%). For factors influencing CCS, nine key themes were identified and organized into four categories: (1) patient factors, (2) HCP factors, (3) health system factors and (4) health promotion factors. Key themes commonly highlighted by study participants were related to patients' preferences and acceptance for screening, the processes of delivering CCS, the national priority for cervical cancer and the effectiveness of existing health promotion efforts. Five key themes were identified for CCS innovations. Self-sampling was viewed favorably to increase CCS uptake, while primary HPV screening with HPV partial genotyping had higher sensitivities to detect pre-cancers and cancers compared to cytology. Extended HPV genotyping beyond HPV16/18 could play an important role in CCS with increasing HPV vaccination coverage, as well as in the management of persistent HPV infection.ConclusionIn Singapore, HCPs face multiple challenges for CCS in practice. Insights from this study are directly relevant to, and useful for developing policies around national CCS programs and treatment guidelines

Factors determining the survival of nasopharyngeal carcinoma with lung metastasis alone: does combined modality treatment benefit?

<p>Abstract</p> <p>Background</p> <p>Nasopharyngeal carcinoma (NPC) with lung metastasis alone has been reported as a relatively favorable prognostic group, and combined modality treatment might be indicated for selected cases. However, the prognostic factors determining survival of this group and the indication of combined therapy have not been thoroughly studied.</p> <p>Methods</p> <p>We retrospectively reviewed 246 patients of NPC with lung metastasis(es) alone presented at diagnosis or as the first failure after primary treatment from 1993 to 2008 in an academic tertiary hospital. Univariate and multivariate survival analyses of post-metastasis survival (PMS) and overall survival (OS) were carried out to determine the prognostic factors.</p> <p>Results</p> <p>The 3-year, 5-year, and 10-year of PMS and OS for the whole cohort were 34.3%, 17.0%, 8.6% and 67.8%, 45.4%, 18.5%, respectively. The median PMS (45.6 months <it>vs</it>. 23.7 months) and OS (73.7 months <it>vs</it>. 46.2 months) of patients treated with combined therapy was significantly longer than that of those treated with chemotherapy alone (<it>P </it>< 0.001). Age, disease-free interval (DFI) and treatment modality were evaluated as independent prognostic factors of OS, while only age and treatment modality retain their independent significance in PMS analysis. In stratified survival analysis, compared to chemotherapy alone, combined therapy could benefit the patients with DFI > 1 year, but not those with DFI ≤ 1 year.</p> <p>Conclusions</p> <p>Age ≤ 45 years, DFI > 1 year, and the combined therapy were good prognostic factors for NPC patients with lung metastasis(es) alone. The combination of local therapy and the basic chemotherapy should be considered for these patients with DFI > 1 year.</p

Heterozygosity for Pten Promotes Tumorigenesis in a Mouse Model of Medulloblastoma

BACKGROUND: Recent publications have described an important role for cross talk between PI-3 kinase and sonic hedgehog signaling pathways in the pathogenesis of medulloblastoma. METHODOLOGY/PRINCIPAL FINDINGS: We crossed mice with constitutive activation of Smoothened, SmoA1, with Pten deficient mice. Both constitutive and conditional Pten deficiency doubled the incidence of mice with symptoms of medulloblastoma and resulted in decreased survival. Analysis revealed a clear separation of gene signatures, with up-regulation of genes in the PI-3 kinase signaling pathway, including downstream activation of angiogenesis in SmoA1+/-; Pten +/- medulloblastomas. Western blotting and immunohistochemistry confirmed reduced or absent Pten, Akt activation, and increased angiogenesis in Pten deficient tumors. Down-regulated genes included genes in the sonic hedgehog pathway and tumor suppressor genes. SmoA1+/-; Pten +/+ medulloblastomas appeared classic in histology with increased proliferation and diffuse staining for apoptosis. In contrast, Pten deficient tumors exhibited extensive nodularity with neuronal differentiation separated by focal areas of intense staining for proliferation and virtually absent apoptosis. Examination of human medulloblastomas revealed low to absent PTEN expression in over half of the tumors. Kaplan-Meier analysis confirmed worse overall survival in patients whose tumor exhibited low to absent PTEN expression. CONCLUSIONS/SIGNIFICANCE: This suggests that PTEN expression is a marker of favorable prognosis and mouse models with activation of PI-3 kinase pathways may be important tools for preclinical evaluation of promising agents for the treatment of medulloblastoma

Self-oligomerization regulates stability of survival motor neuron protein isoforms by sequestering an SCF^Slmb degron

Spinal muscular atrophy (SMA) is caused by homozygous mutations in human SMN1. Expression of a duplicate gene (SMN2) primarily results in skipping of exon 7 and production of an unstable protein isoform, SMNΔ7. Although SMN2 exon skipping is the principal contributor to SMA severity, mechanisms governing stability of survival motor neuron (SMN) isoforms are poorly understood. We used a Drosophila model system and label-free proteomics to identify the SCFSlmb ubiquitin E3 ligase complex as a novel SMN binding partner. SCFSlmb interacts with a phosphor degron embedded within the human and fruitfly SMN YG-box oligomerization domains. Substitution of a conserved serine (S270A) interferes with SCFSlmb binding and stabilizes SMNΔ7. SMA-causing missense mutations that block multimerization of full-length SMN are also stabilized in the degron mutant background. Overexpression of SMNΔ7S270A, but not wild-type (WT) SMNΔ7, provides a protective effect in SMA model mice and human motor neuron cell culture systems. Our findings support a model wherein the degron is exposed when SMN is monomeric and sequestered when SMN forms higher-order multimers

Exploration of Shared Genetic Architecture Between Subcortical Brain Volumes and Anorexia Nervosa

In MRI scans of patients with anorexia nervosa (AN), reductions in brain volume are often apparent. However, it is unknown whether such brain abnormalities are influenced by genetic determinants that partially overlap with those underlying AN. Here, we used a battery of methods (LD score regression, genetic risk scores, sign test, SNP effect concordance analysis, and Mendelian randomization) to investigate the genetic covariation between subcortical brain volumes and risk for AN based on summary measures retrieved from genome-wide association studies of regional brain volumes (ENIGMA consortium, n = 13,170) and genetic risk for AN (PGC-ED consortium, n = 14,477). Genetic correlations ranged from − 0.10 to 0.23 (all p > 0.05). There were some signs of an inverse concordance between greater thalamus volume and risk for AN (permuted p = 0.009, 95% CI: [0.005, 0.017]). A genetic variant in the vicinity of ZW10, a gene involved in cell division, and neurotransmitter and immune system relevant genes, in particular DRD2, was significantly associated with AN only after conditioning on its association with caudate volume (pFDR = 0.025). Another genetic variant linked to LRRC4C, important in axonal and synaptic development, reached significance after conditioning on hippocampal volume (pFDR = 0.021). In this comprehensive set of analyses and based on the largest available sample sizes to date, there was weak evidence for associations between risk for AN and risk for abnormal subcortical brain volumes at a global level (that is, common variant genetic architecture), but suggestive evidence for effects of single genetic markers. Highly powered multimodal brain- and disorder-related genome-wide studies are needed to further dissect the shared genetic influences on brain structure and risk for AN

Targeted gene sanger sequencing should remain the first-tier genetic test for children suspected to have the five common X-linked inborn errors of immunity

DATA AVAILABILITY STATEMENT : The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding author.To address inborn errors of immunity (IEI) which were underdiagnosed in resource-limited regions, our centre developed and offered free genetic testing for the most common IEI by Sanger sequencing (SS) since 2001. With the establishment of The Asian Primary Immunodeficiency (APID) Network in 2009, the awareness and definitive diagnosis of IEI were further improved with collaboration among centres caring for IEI patients from East and Southeast Asia. We also started to use whole exome sequencing (WES) for undiagnosed cases and further extended our collaboration with centres from South Asia and Africa. With the increased use of Next Generation Sequencing (NGS), we have shifted our diagnostic practice from SS to WES. However, SS was still one of the key diagnostic tools for IEI for the past two decades. Our centre has performed 2,024 IEI SS genetic tests, with in-house protocol designed specifically for 84 genes, in 1,376 patients with 744 identified to have disease-causing mutations (54.1%). The high diagnostic rate after just one round of targeted gene SS for each of the 5 common IEI (X-linked agammaglobulinemia (XLA) 77.4%, Wiskott–Aldrich syndrome (WAS) 69.2%, X-linked chronic granulomatous disease (XCGD) 59.5%, X-linked severe combined immunodeficiency (XSCID) 51.1%, and X-linked hyper-IgM syndrome (HIGM1) 58.1%) demonstrated targeted gene SS should remain the first-tier genetic test for the 5 common X-linked IEI.The Hong Kong Society for Relief of Disabled Children and Jeffrey Modell Foundation.http://www.frontiersin.org/Immunologyam2023Paediatrics and Child Healt

Immunotherapy for Colorectal Cancer

The recent success of anti-PD1 drugs in metastatic colorectal cancer patients with mismatch repair deficiency generated overwhelming enthusiasm for immunotherapy in the disease. However, patients with mismatch repair deficient colorectal cancer represent only a small subset of the metastatic population. Current research focuses on advancing immunotherapy to earlier stages of the disease including adjuvant and first-line metastatic settings, and on inducing sensitivity to immune checkpoint inhibitor therapy through a combinatorial approach. Here, we review the contemporary understanding of the immune and molecular landscape in colorectal cancer and discuss ongoing clinical trials evaluating novel combination regimens based on immune checkpoint inhibitors