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Background The polymeric immunoglobulin receptor (pIgR) is a transmembrane transporter of polymeric IgA through the intestinal epithelium. Its overexpression has been reported in several cancers, but its role as a diagnostic and prognostic biomarker of oncogenesis is currently unclear. Method A literature search was conducted to summarize the functions of pIgR, its expression levels, and its clinical implications. Results pIgR expression has previously been investigated by proteomic analysis, RNA sequencing, and tissue microarray at the level of both RNA and protein in various cancers including pancreatic, esophageal, gastric, lung, and liver. However, studies have reported inconsistent results on how pIgR levels affect clinical outcomes such as survival rate and chemotherapy resistance. Possible explanations include pIgR mRNA levels being minimally correlated with the rate of downstream pIgR protein synthesis, and the diversity of antibodies used in immunohistochemistry studies further magnifying this ambiguity. In ovarian cancer cells, the transcytosis of IgA accompanied a series of transcriptional changes in intracellular inflammatory pathways that inhibit the progression of cancer, including the upregulation of IFN-gamma and downregulation of tumor-promoting ephrins. These findings suggest that both the levels of pIgR and secreted IgA from tumor-infiltrating B cells affect clinical outcomes. Conclusion Overall, no direct correlation was observed between the levels of pIgR inside tumor tissue and the clinical features in cancer patients. Measuring pIgR protein levels with a more specific and possibly chemically defined antibody, along with tumoral IgA, is a potential solution to better understand the pathways and consequences of pIgR overexpression in cancer cells.

Adding non-adsorbing polymers to hard microsphere dispersions generates osmotic depletion attractions that can be quantitatively predicted and designed to manipulate colloidal phase behavior. Whether depletion described by classical theories is the mechanism for polymer-mediated nanosphere attractions is less evident. Colloidal hard nanospheres and non-adsorbing polymers are challenging to realize given the diverse interactions typically present in nanoparticle dispersions. Here, we use small-angle X-ray scattering to assess whether the depletion mechanism holds at the nanoscale, leveraging a recent finding that uncharged, oleate-capped indium oxide nanocrystals exhibit near-hard-sphere interactions in toluene. Classical modeling of polystyrene depletant as penetrable spheres predicts depletion induced phase boundaries, nanocrystal second osmotic virial coefficients, and colloidal structuring in agreement with experiments for polymer radii of gyration up to 80\\\% of the nanocrystal radius. Experimentally observed weakening of depletion interactions for larger polymer-to-nanocrystal size ratios qualitatively follows theoretical predictions that account for how polymer physics influences depletant interactions.

Omission of impersonal direct object has been observed in Spanish spoken in Paraguay. This linguistic phenomenon has been previously analyzed as a result of direct transfer from a similar syntactic feature of Guaraní, the language with which Spanish has coexisted for more than four centuries in Paraguay. Nevertheless, the data collected indicated that the omission of [-person] direct object clitics is present in the speech of all socio-educational classes, among both bilinguals and monolingual Spanish speakers. Additionally, the occurrence of the same phenomenon in other regional varieties of Spanish, as well as another Romance language and its dialect proves that the external explanation, namely Guaraní substratum theory, cannot be the only genetic cause behind the origin of this phenomenon.

We constructed B cell receptor (BCR) repertoires in silico using peripheral blood (PB) samples collected from 44 Alzheimer’s Disease (AD) patients at baseline and 37 patients at follow-up. For the control group (CG), we used BCR repertoire data from the chronologically collected PB samples of 55 healthy volunteers vaccinated with SARS-CoV-2 mRNA. The AD patients shared 3,983 stereotypic non-naïve BCR clonotypes not found in CG, and their degree of overlap between patient pairs were significantly higher than that of CG pairs, even with the SARS-CoV-2 spike protein triggering a concerted BCR response. Twenty stereotypic non-naïve AD patient-specific BCR clonotypes co-existed in more than four patients and persisted throughout two sampling points. One of these BCR clonotypes encoded an antibody reactive to the Aβ42 peptide. Our findings strongly suggest that AD patients are exposed to common (auto)antigens associated with disease pathology, and their BCR repertoires show unique signatures with diagnostic potential.

Omission of impersonal direct object has been observed in Spanish spoken in Paraguay. This linguistic phenomenon has been previously analyzed as a result of direct transfer from a similar syntactic feature of Guarani, the language with which Spanish has coexisted for more than four centuries in Paraguay. Nevertheless, the data collected indicated that the omission of [-person] direct object clitics is present in the speech of all socio-educational classes, among both bilinguals & monolingual Spanish speakers. Additionally, the occurrence of the same phenomenon in other regional varieties of Spanish, as well as another Romance language & its dialect, proves that the external explanation, namely Guarani substratum theory, cannot be the only genetic cause behind the origin of this phenomenon. 7 Tables, 1 Figure, 90 References. Adapted from the source document

This study presents an analysis of morphosyntactic peculiarities of Paraguayan Spanish, and considers their possible multiple origins. I consider the influence of the Guarani language with which Spanish has coexisted for more than four centuries in a society which is still composed of 48.9% Spanish-Guarani bilinguals. However, I show that the interference of the Guarani language on local Spanish or other genetic causes of an external nature cannot provide a complete explanation or formulate a cohesive argument for the linguistic phenomena under consideration in this study. I also argue that an internal explanation is incomplete for the analysis of some features found in Paraguayan Spanish. In view of this, in this study I use the theoretical framework of multiple causation, considering internal and external factors equally, and not favoring one explanation over another. Additionally, I study the genesis and development of the linguistic structures considered here, examining their diachronic context. Synchronically, I examine data collected in Paraguay, as well as the use of the same features in other Spanish dialects and Romance languages. Chapter 1 presents the historical background of the unique linguistic situation found in Paraguay. This diachronic information is fundamental to a better understanding of the complex synchronic situation, the concept of national bilingualism, and hypotheses for the genesis of the morphosyntactic structures discussed in chapters 2-4. With this as a foundation, chapter 2 turns to the phenomenon called voseo. The use of vos, originally a second person plural pronoun, and its verb forms, instead of tu as the second person singular pronoun, is one of the peculiar phenomena of Paraguayan Spanish. I present a diachronic evolution of the pronominal and verb forms of voseo. This chapter also discusses another related feature, the alternation of the informal second person singular, vos, with usted, the formal one. I argue that this alternation is the result of the linguistic situation where there are languages in contact. In the case of Paraguay, the interference of Guarani, which lacks the distinction between the second person singular of respect and familiarity, is a crucial factor. Chapter 3 examines leismo, les $>$ le, and (-human) object drop. I study the genesis and provide a diachronic account of the structures in the 16th-century Spanish texts, as well as modern registers in different Spanish dialects and other languages to prove that a strictly substratal theory cannot offer a complete explanation of why these phenomena are maintained in the Spanish spoken in Paraguay. Finally, in chapter 4 I discuss three linguistic structures that have been previously considered as the exclusive results of interference via direct transfer from Guarani: double negation (e.g., Nadie no vino), use of the preposition en with directional verbs (e.g., Voy en Asuncion), and the combination of indefinite article or demonstrative adjective + possessive + noun (e.g., Un mi hermano, Ese mi amigo).

Immune response during the progression of premalignant lesions and their molecular subtype to colorectal cancer (CRC) remains unclear. Using gene expression data from 135 normal (NLs), 176 conventional adenomas (AD), 42 serrated polyps (SER), and 2760 CRC samples, we estimated overall immune activity (ImmuneScore) and tumor-infiltrating lymphocyte (TIL) abundance using the xCell tool. We evaluated association of the ImmuneScore and TILs with CRC progression using adjusted multivariable regression models. Immunohistochemistry (IHC) staining for five immunological markers was conducted on NL, early- and late-stage AD, and carcinoma tissues from 75 study participants. The consensus molecular subtypes (CMS) of adenomas and carcinomas were classified using random forest methods, and the association of immune activity with CRC progression was assessed. Immune activity consistently decreased from NLs through premalignant lesions to adenocarcinoma, more prominently in AD than SER (AD vs. NL: odds ratio = 0.86, 95% CI = 0.84‒0.88; SER vs. NL: 0.89, 0.85‒0.93). Similar patterns were observed in B cells, CD4 + effector memory T cells, CD8 + naïve T cells, and CD8 + cytotoxic T cells. IHC staining of these immunological markers verified their roles in CRC progression. Our analysis revealed that CMS3 is a major subtype of AD. Consistently, higher immune activity was observed in premalignant lesions than in CRCs of the CMS3 subtype. This study provides additional insights into alterations in immune response and their important role in CRC premalignant lesion progression and subtypes.

The importance of cholesterol ester synthesis by acyl CoA:cholesterol acyltransferase (ACAT) enzymes in intestinal and hepatic cholesterol metabolism has been unclear. We now demonstrate that ACAT2 is the major ACAT in mouse small intestine and liver, and suggest that ACAT2 deficiency has profound effects on cholesterol metabolism in mice fed a cholesterol-rich diet, including complete resistance to diet-induced hypercholesterolemia and cholesterol gallstone formation. The underlying mechanism involves the lack of cholesterol ester synthesis in the intestine and a resultant reduced capacity to absorb cholesterol. Our results indicate that ACAT2 has an important role in the response to dietary cholesterol, and suggest that ACAT2 inhibition may be a useful strategy for treating hypercholesterolemia or cholesterol gallstones.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a provisional entity in the 2017 World Health Organization classifications. To further elucidate the clinicopathologic features of this new disease, we carried out a retrospective, multicenter analysis of 42 patients with MEITL. The median age of the patients was 59 years (range, 20–84 years), and 27 patients (64 %) were male. Thirty-two patients (76 %) were Ann-Arbor stages I–II and 28 (67 %) were Lugano stages I–II1&2. The most frequent site of involvement was the jejunum (N = 21). Most cases expressed CD8 (79 %) and CD56 (95 %) and did not express CD30 (5 %) or EBER (0 %). The median progression-free survival was 6.9 months (95 % CI 4.3–9.6); the median OS was 14.8 months (2.4–27.2). Thirty-two patients (76 %) underwent surgery and 37 (88 %) received chemotherapy. A complete response (CR) rate was 38 %. Sixteen patients had undergone autologous stem cell transplantation (ASCT). Relapse or progression was documented in 24 cases, most frequently in the primary site (N = 23). Four cases showed central nervous system relapse. Age over 55 years, poor performance scale, advanced Lugano stage (IIE–IV), not achieving CR, and not receiving ASCT were associated with inferior OS. While the optimal management of MEITL remains undetermined, achieving CR and consolidative ASCT seem essential. As CHOP might be insufficient for achieving CR, more efficient combinations should be investigated. Additionally, considering the frequent local failure and CNS relapse, novel therapeutic approaches are required to improve survival.