Sulfated fucans attract increasing research interests in recent decades for their various physiological activities. Fucanases are indispensable tools for the investigation of sulfated fucans. Herein, a novel GH168 family endo-1,3-fucanase was cloned from the genome of marine bacterium Wenyingzhuangia fucanilytica. The expressed protein Fun168D was a processive endo-acting enzyme. Ultra performance liquid chromatography-high resolution mass spectrum and NMR analyses revealed that the enzyme cleaved the α-1 → 3 bonds between α-l-Fucp(2OSO3-) and α-l-Fucp(2OSO3-) in sulfated fucan from Isostichopus badionotus, and α-1 → 3 bonds between α-l-Fucp(2OSO3-) and α-l-Fucp(2,4OSO3-) in sulfated fucan from Holothuria tubulosa. Fun168D would prefer to accept α-l-Fucp(2,4OSO3-) than α-l-Fucp(2OSO3-) at subsite +1, and could tolerate the absence of fucose residue at subsite +2. The novel cleavage specificity and hydrolysis pattern revealed the presence of diversity within the GH168 family, which would facilitate the development of diverse biotechnological tools for the molecule tailoring of sulfated fucan.

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.

OBJECTIVE: This study presents a novel classification of the anatomical subsites of the tonsillar fossa and discusses their associations with post-tonsillectomy hemorrhage (PTH) after extracapsular tonsillectomy.
METHODS: Coblation tonsillectomy was performed on three adult cadavers and the anatomical subsites of the tonsillar fossa based on the distribution of the tonsillar feeding artery: the upper pole (subsite A), most of the tonsil body (subsite B), the inferior tonsil body (subsite C), and components of the lower pole (subsites D and E). Extracapsular tonsillectomy was prospectively performed using various surgical techniques and PTH was evaluated.
RESULTS: A cadaveric study revealed that the intra- and extra-capsular vessel topographies were essentially identical. Although the demarcation lines varied either up or down by a few millimeters, the arterial vascular network was particularly dense at subsites D and E, and the vessel diameter at these subsites was significantly greater than at subsite C and also (especially) at subsite E. Of 680 patients who underwent tonsillectomy, PTH developed early in 13 (31.7%) and late in 28 (68.3%). Surgical interventions were required by 29/41 patients (70.7%). Subsites D and E were the most common subsites of late PTH and PTH that required intervention. Such intervention was rarely necessary when PTH developed at subsite A or B.
CONCLUSIONS: The new classification of the anatomical subsites of the tonsillar fossa aids inexperienced surgeons and provides an anatomical rationale for variation in surgical technique that minimizes vascular injury, thus improving safety.

Agarans are sulfated galactans extracted from red algae with high structural complexity, of which natural methylation often occurs on the O-6 position of its β-d-galactopyranose units. Although many agaran degrading enzymes, including agarases and porphyranases, have been characterized, little attention has been paid to the tolerance of methyl groups at cleavage subsites. In this study, the structure of GH86 β-agarase Aga86A_Wa from Wenyingzhuangia aestuarii was determined by X-ray crystallography and investigated from a structural biology perspective. The structure indicated that an accommodation pocket formed by F367, Y280, and Q326 at subsite -1 contributes to the methyl-galactose tolerance of Aga86A_Wa. Furthermore, we found that similar accommodation pockets were present in the structures of two other GH86 enzymes BuGH86 from Bacteroides uniformis and BpGH86A from Phocaeicola plebeius, and their previously undisclosed methyl-galactose tolerance was verified, validating the function of the pockets. Phylogenetic analysis, structural modeling, and hydrolysis product characterization suggested that the methyl-galactose accommodation capacity at subsite -1 was prevalent in GH86 members. These findings achieve a better understanding of the function and mechanism of GH86 agaran degrading enzymes, and will facilitate the precise preparation of agaran oligosaccharides by employing defined tools.

Tobacco use and alcohol consumption are still important risk factors for head and neck cancer (HNC) in developing countries, even though decreasing in tobacco prevalence. Recently, an increased incidence of oropharyngeal cancer due to human papilloma virus (HPV) infection has attracted attention in advanced countries, including the United States and Europe. However, few studies have evaluated trends in the incidence of HNC by subsite in Japan.
Accordingly, we evaluated these trends in Japan using data from population-based cancer registries. We compiled population-based incidence data from the Monitoring of Cancer Incidence in Japan Project, based on data from 19 population-based cancer registries. Number of incident cases and age-standardized incidence rates of HNC were estimated by subsite, namely lip, oral cavity, salivary glands, nasopharynx, oropharynx, hypopharynx, larynx, nasal and paranasal cavity, middle ear and NOS. Trends in agestandardized incidence rates were characterized using the Joinpoint analysis.
Among both sexes, oral cavity cancer, salivary gland cancer, and oropharyngeal cancer showed an upward trend (oral cavity: annual percent change (APC) 1.2% for men and APC 1.9% for women; salivary gland: APC 2.2% for men and APC 3.1% for women; oropharynx: APC 5.0% for men and APC 7.6% for women). Additionally, hypopharyngeal cancer showed an upward trend for men (APC 4.1%), and nasopharyngeal cancer and laryngeal cancer showed a downward trend for men (nasopharynx: APC -2.7%; larynx: -1.1%).
These findings will assist in focusing on the individual prevention of HNC.

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.

OBJECTIVE: This study assessed the influence of tumor localization of small bowel adenocarcinoma on survival after surgical resection.
METHODS: Patients with resected small bowel adenocarcinoma, ACJJ stage I-III, were identified from the Surveillance, Epidemiology, and End Results database from 2004 to 2013. The impact of tumor localization on overall and cancer-specific survival was assessed using Cox proportional hazard regression models with and without risk-adjustment and propensity score methods.
RESULTS: Adenocarcinoma was localized to the duodenum in 549 of 1025 patients (53.6%). There was no time trend for duodenal localization (P = 0.514). The 5-year cancer-specific survival rate was 48.2% (95%CI: 43.3-53.7%) for patients with duodenal carcinoma and 66.6% (95%CI: 61.6-72.1%) for patients with cancer located in the jejunum or ileum. Duodenal localization was associated with worse overall and cancer-specific survival in univariable (HR = 1.73; HR = 1.81, respectively; both P < 0.001), multivariable (HR = 1.52; HR = 1.65; both P < 0.001), and propensity score-adjusted analyses (HR = 1.33, P = 0.012; HR = 1.50, P = 0.002). Furthermore, young age, retrieval of more than 12 regional lymph nodes, less advanced stage, and married matrimonial status were positive, independent prognostic factors.
CONCLUSIONS: Duodenal localization is an independent risk factor for poor survival after resection of adenocarcinoma.