There are well-established disparities in colorectal cancer (CRC) outcomes between White and Black patients; however, assessments of CRC disparities for other racial/ethnic groups are limited.
The Surveillance, Epidemiology, and End Results database identified patients aged 50-74 years with CRC adenocarcinoma from 2000 to 2019. Trends in age-adjusted incidence rates were computed by stage at diagnosis and subsite across five broad race/ethnic groups (White, Black, Asian/Pacific Islander [API], American Indian/Alaskan Native [AIAN], and Hispanic) and four API subgroups (East Asian, Southeast Asian, South Asian, and Pacific Islander) Multivariable logistic regression evaluated associations between race/ethnicity and diagnosis stage. Multivariable Cox proportional hazards models assessed differences in cause-specific survival (CSS).
Hispanic, AIAN, Southeast Asian, Pacific Islander, and Black patients were 3% to 28% more likely than Whites to be diagnosed with distant stage CRC, whereas East Asian and South Asians had similar or lower risk of distant stage CRC. From Cox regression analysis, Black, AIAN, and Pacific Islanders also experienced worse CSS, while East Asian and South Asian patient groups experienced better CSS. No significant differences in CSS were observed among Hispanic, Southeast Asian, and White patients. When stratified by stage, Black patients had worse CSS across all stages (early, hazard ratio (HR) = 1.38; regional, HR = 1.22; distant, HR: 1.07, p < 0.05 for all).
Despite advances in CRC screening, treatment and early detection efforts, marked racial/ethnic disparities in incidence, stage at diagnosis, and survival persist. Findings demonstrate the extent to which aggregating heterogenous populations masks significant variability in CRC outcomes within race/ethnic subgroups.

Cutaneous head and neck melanoma is a separate subgroup of cutaneous melanoma that has a worse prognosis than other primary sites. The aim of this article is to examine the significance of sex and site of primary lesion as additional risk factors. Primary localization distribution and metastatic disease in the neck in a retrospective cohort of 159 patients with cutaneous head and neck malignant melanoma were analyzed. Men develop primary melanoma more frequently than women in the left peripheral head and neck regions (P = .0364), as well as clinically visible and occult metastatic disease in the left side of the neck (P = .0138). Patients with clinically occult regional metastatic disease showed a significantly poorer survival rate than the rest of the group that underwent elective neck dissections (P = .0270). Left-sided disease in male patients may be an additional risk factor in cutaneous head and neck melanoma. Performing elective neck dissections in high-risk patients might identify patients with occult metastatic disease and worse prognosis but does not offer any significant therapeutic benefit.

Unspliced XBP1 mRNA encodes XBP1u, the transcriptionally inert variant of the unfolded protein response (UPR) transcription factor XBP1s. XBP1u targets its mRNA-ribosome-nascent-chain-complex to the endoplasmic reticulum (ER) to facilitate UPR activation and prevents overactivation. Yet, its membrane association is controversial. Here, we use cell-free translocation and cellular assays to define a moderately hydrophobic stretch in XBP1u that is sufficient to mediate insertion into the ER membrane. Mutagenesis of this transmembrane (TM) region reveals residues that facilitate XBP1u turnover by an ER-associated degradation route that is dependent on signal peptide peptidase (SPP). Furthermore, the impact of these mutations on TM helix dynamics was assessed by residue-specific amide exchange kinetics, evaluated by a semi-automated algorithm. Based on our results, we suggest that SPP-catalyzed intramembrane proteolysis of TM helices is not only determined by their conformational flexibility, but also by side-chain interactions near the scissile peptide bond with the enzyme\'s active site.

BACE1 is a key aspartic protease that cleaves the amyloid precursor protein to generate of the amyloid peptide that is believed to be responsible for the Alzheimer\'s disease amyloid cascade. It is thus recognized as a promising therapeutic target for Alzheimer\'s disease treatment, and large efforts have been made in the discovery of novel BACE1 inhibitors. This Review presents a systematic mining of BACE1 inhibitors based on 354 crystal structures of the BACE1 catalytic domain in complex with ligands in the Protein Data Bank. A thorough exploration on the frequency as well as the patterns of residue-ligand interactions enables us to subdivide the ligand binding pocket into 10 subsites and then identify favorable substructures of ligands for each subsite. In addition, it is found that the assembly of subsites with an 8-like shape is responsible to bind all inhibitors and four major ligand binding modes are revealed. Thus, such a systematic survey deepens our understanding of the structural requirements for establishment of BACE1-ligand interactions that determine the affinity of a ligand to BACE1, which is pivotal for structure-based lead optimization and design of novel inhibitors.

To determine if there are differences in mortality from oral cavity squamous cell carcinoma (OCSCC) based on oral cavity (OC) subsites.
Using the Surveillance, Epidemiology, and End Results Program (SEER) 9 database, patients with sequence number 0 or 1 squamous cell OCSCC were analyzed by OC subsite for 5-year cause-specific mortality (CSM) from OCSCC. Proportional hazards regression determined the association between 5-year CSM and OC subsites while controlling for treatment modality, stage, and demographic characteristics using hazard ratios. Significance was set at alpha = 0.05.
20,647 OC patients were included in the regression analysis. The most commonly diagnosed sites were floor of mouth (34.4%) and oral tongue (34.3%). Floor of mouth, upper gum, and retromolar trigone were associated with lower CSM compared to oral tongue. Not receiving surgery and receiving radiation were associated with increased CSM, and CSM increased with cancer staging when distant or regional disease was compared to localized disease. Also, patients diagnosed at 60 years or older and black patients had increased CSM.
Among OCSCC patients, those with oral tongue cancer are more likely to experience CSM than patients with floor of mouth, upper gum, and retromolar trigone cancer. It is important to understand these mortality related differences in the management of OCSCC patients. Understanding subsite-specific mortality may benefit prognosis counseling of OCSCC patients and elicit subsite-directed research as a means to improve outcomes.
NA Laryngoscope, 129:1400-1406, 2019.

Family 81 glycoside hydrolases (GHs), which are known to cleave β-1,3-glucans, are found in archaea, bacteria, eukaryotes, and viruses. Here we examine the structural and functional features of the GH81 catalytic module, BhGH81, from the Bacillus halodurans protein BH0236 to probe the molecular basis of β-1,3-glucan recognition and cleavage. BhGH81 displayed activity on laminarin, curdlan, and pachyman, but not scleroglucan; the enzyme also cleaved β-1,3-glucooligosaccharides as small as β-1,3-glucotriose. The crystal structures of BhGH81 in complex with various β-1,3-glucooligosaccharides revealed distorted sugars in the -1 catalytic subsite and an arrangement consistent with an inverting catalytic mechanism having a proposed conformational itinerary of 2S0 → 2,5B‡ → 5S1. Notably, the architecture of the catalytic site, location of an adjacent ancillary β-1,3-glucan binding site, and the surface properties of the enzyme indicate the likely ability to recognize the double and/or triple-helical quaternary structures adopted by β-1,3-glucans.

Here we report the first crystal structure of a secretory α-glucoside hydrolase isolated from Pseudoalteromonas sp. K8, PspAG97A, which belongs to glycoside hydrolase family 97 and exhibits halophilic property. PspAG97A lacks an acidic surface, that is considered essential for protein stability at high salinity. Interestingly, PspAG97A unusually contains a chloride ion coordinated by the guanidinium group of Arg171 and the main chain amide groups of Tyr172 and Glu173 at the active site. The structures of PspAG97A complexed with acarbose and panose demonstrate that residues Glu173, Arg171 and Asn170 for subsite +1 decide the substrate specificity of the enzyme for the α-1,6-glucosidic linkage. Structural alterations observed in the R171K variant and enzyme kinetic experiments focusing on chloride assisted activation suggest that the active site chloride serves to properly orient Glu173, Arg171 and Asn170 to facilitate substrate recognition. Furthermore, the chloride assists the binding of Glu173 to the conserved calcium ion and plays an essential role in properly positioning the base catalyst Glu456. In sum, our results provide valuable insight into the structural basis of protein halophilicity.

Thermobifida fusca is a well-known cellulose-degrading actinomycete, which produces various glycoside hydrolases for this purpose. However, despite the presence of putative chitinase genes in its genome, T. fusca has not been reported to grow on chitin as sole carbon source. In this study, a gene encoding a putative membrane-anchored GH18 chitinase (Tfu0868) from T. fusca has been cloned and overexpressed in Escherichia coli. The protein was produced as SUMO fusion protein and, upon removal of the SUMO domain, soluble pure TfChi18A was obtained with yields typically amounting to 150mg per litre of culture. The enzyme was found to be relatively thermostable (apparent Tm=57.5°C) but not particularly thermoactive, the optimum temperature being 40-45°C. TfChi18A bound to α- and β-chitin and degraded both these substrates. Interestingly, activity towards colloidal chitin was minimal and in this case, substrate inhibition was observed. TfChi18A also cleaved soluble chito-oligosaccharides and showed a clear preference for substrates having five sugars or more. While these results show that TfChi18A is a catalytically competent GH18 chitinase, the observed catalytic rates were low compared to those of well-studied GH18 chitinases. This suggests that TfChi18A is not a true chitinase and not likely to endow T. fusca with the ability to grow on chitin.

BACKGROUND: The incidence of gastric cancer has declined over the past decades. Little is known about trends by site and histological subtype. The aim of this study was to analyze changes in gastric cancer incidence patterns in a French well-defined population.
METHODS: Data on patients with an epithelial gastric cancer diagnosed between 1982 and 2011 were collected by the population-based digestive cancer registry of Burgundy (n = 4694). Time trends in gastric cancer incidence by period of diagnosis and birth cohort were analyzed by sex, subsite, and histological type.
RESULTS: There was a decrease in incidence rates for antral carcinomas (-2.6 % per year in males, -2.5 % per year in females; p < 0.001) and corpus carcinomas (-3.3 % and -3.2 %, respectively; p < 0.001). Annual percentage changes were not significant for fundus carcinomas in both sexes and cardia carcinoma in females, although they increased in males (+1.0 % per year; p < 0.02).When comparing the 1900 cohort and the 1950 cohort, there was a five- to sevenfold decrease in the cumulative risk at 0-79 years for corpus and antral carcinomas in both sexes and a threefold decrease for fundus carcinomas. There were minor variations for cardia carcinomas. There was a decrease of incidence both by period of diagnosis and by birth cohort for adenocarcinoma and colloid carcinoma. It was more marked for undifferentiated carcinoma. The variation for signet-ring carcinoma was minor.
CONCLUSIONS: Temporal variations in incidence rates of gastric cancer differed according to subsite and histology, suggesting different etiological factors. Available analytical studies provide an explanation for the reported trends by subsite.

Colorectal cancer (CRC) exhibits differences in incidence, pathogenesis, molecular pathways and outcome depending on the location of the tumor. This review focuses on the latest developments in epidemiological and scientific studies, which have enhanced our understanding on the underlying genetic and immunological differences between the proximal (right-sided) colon and the distal (left-sided) colorectum. The different ways in which environmental risk factors influence the pathogenesis of CRC depending on its location and the variations in surgical and oncological outcomes are also discussed in this review. In the current era of personalized medicine, we aim to reiterate the importance of tumor location in management of CRC and the implication on future clinical and scientific research.