Evidence for a novel neuronal mechanism driving Alzheimer's disease, upstream of amyloid.

This perspective offers an alternative to the amyloid hypothesis in the etiology of Alzheimer's disease (AD). We review evidence for a novel signaling mechanism based on a little-known peptide, T14. T14 could drive neurodegeneration as an aberrantly activated process of plasticity selective to interconnecting subcortical nuclei, the isodendritic core, where cell loss starts at the pre-symptomatic stages of the disease. Each of these cell groups has the capacity to form T14, which can stimulate production of p-Tau and ß-amyloid, suggestive of an upstream driver of neurodegeneration. Moreover, results in an animal AD model show that antagonism of T14 with a cyclated variant, NBP14, prevents formation of ß-amyloid, and restores cognitive function to that of wild-type counterparts. Any diagnostic and/or therapeutic strategy based on T14-NBP14 awaits validation in clinical trials. However, an understanding of this novel signaling system could bring much-needed fresh insights into the progression of cell loss underlying AD. HIGHLIGHTS: The possible primary mechanism of neurodegeneration upstream of amyloid. Primary involvement of selectively vulnerable subcortical nuclei, isodendritic core. Bioactive peptide T14 trophic in development but toxic in context of mature brain. Potential for early-stage biomarker to detect Alzheimer's disease. Effective therapeutic halting neurodegeneration, validated already in 5XFAD mice.

A rare case of IgA lambda multiple myeloma in a 32-year-old woman with t(14;16) translocation associated with kidney injury and non-albumin proteinuria.

BACKGROUND: Multiple myeloma (MM) is a malignant disorder characterized by monoclonal differentiated plasma cells. While it is more commonly diagnosed in elderly individuals, it can also affect younger populations, though with a lower incidence. CASE PRESENTATION: Here, we present the case of a 32-year-old woman diagnosed with IgA lambda MM. She presented with fatigue, nausea, acute kidney injury (AKI) with a rapid increase in creatinine, and anemia. A kidney biopsy was done to rule out a rapidly progressive glomerular disease and a diagnosis was thus reached. A genetic workup revealed t(14;16) translocation and an extra copy of TP53. The patient received aggressive intravenous steroids and intravenous fluid resuscitation, resulting in an improvement in renal function. Treatment with daratumumab in combination with bortezomib, thalidomide, and dexamethasone was initiated and well tolerated. Despite the generally poor prognosis of IgA MM, our case emphasizes the importance of considering MM in young patients with unexplained kidney injury. CONCLUSION: Early recognition and prompt intervention are essential in managing MM patients, especially in those with high-risk cytogenetic abnormalities. This case serves as a reminder for clinicians to maintain a high index of suspicion for MM, even in younger populations, when presented with unexplained kidney injury.

A Novel Peptide Driving Neurodegeneration Appears Exclusively Linked to the α7 Nicotinic Acetylcholine Receptor.

T14, a 14mer peptide, is significantly increased in the pre-symptomatic Alzheimer's disease brain, and growing evidence implies its pivotal role in neurodegeneration. Here, we explore the subsequent intracellular events following binding of T14 to its target α7 nicotinic acetylcholine receptor (nAChR). Specifically, we test how various experimental manipulations of PC12 cells impact T14-induced functional outcomes. Three preparations were compared: (i) undifferentiated vs. NGF-differentiated cells; (ii) cells transfected with an overexpression of the target α7 nAChR vs. wild type cells; (iii) cells transfected with a mutant α7 nAChR containing a mutation in the G protein-binding cluster, vs. cells transfected with an overexpression of the target α7 nAChR, in three functional assays - calcium influx, cell viability, and acetylcholinesterase release. NGF-differentiated PC12 cells were less sensitive than undifferentiated cells to the concentration-dependent T14 treatment, in all the functional assays performed. The overexpression of α7 nAChR in PC12 cells promoted enhanced calcium influx when compared with the wild type PC12 cells. The α7345-348 A mutation effectively abolished the T14-triggered responses across all the readouts observed. The close relationship between T14 and the α7 nAChR was further evidenced in the more physiological preparation of ex vivo rat brain, where T30 increased α7 nAChR mRNA, and finally in human brain post-mortem, where levels of T14 and α7 nAChR exhibited a strong correlation, reflecting the progression of neurodegeneration. Taken together these data would make it hard to account for T14 binding to any other receptor, and thus interception at this binding site would make a very attractive and remarkably specific therapeutic strategy.

Diverse B-cell tumors associated with t(14;19)(q32;q13)/IGH::BCL3 identified by G-banding and fluorescence in situ hybridization.

We characterized 5 B-cell tumors carrying t(14;19)(q32;q13) that creates the IGH::BCL3 fusion gene. The patients' ages ranged between 55 and 88 years. Two patients presented with progression or recurrence of B-cell chronic lymphocytic leukemia (B-CLL)/small lymphocytic lymphoma (SLL), two with diffuse large B-cell lymphoma (DLBCL) of non-germinal center B-like phenotype, and the remaining one with composite angioimmunoblastic T-cell lymphoma and Epstein-Barr virus-positive DLBCL. The presence of t(14;19)(q32;q13) was confirmed by fluorescence in situ hybridization (FISH), showing colocalization of 3' IGH and 3' BCL3 probes on der(14)t(14;19) and 5' BCL3 and 5' IGH probes on der(19)t(14;19). One B-CLL case had t(2;14)(p13;q32)/IGH::BCL11A, and 2 DLBCL cases had t(8;14)(q24;q32) or t(8;11;14)(q24;q11;q32), both of which generated IGH::MYC by FISH, and showed nuclear expression of MYC and BCL3 by immunohistochemistry. The IGH::BCL3 fusion gene was amplified by long-distance polymerase chain reaction in 2 B-CLL/SLL cases and the breakpoints occurred immediately 5' of BCL3 exon 1 and within the switch region associated with IGHA1. The 5 cases shared IGHV preferentially used in B-CLL cells, but the genes were unmutated in 2 B-CLL/SLL cases and significantly mutated in the remaining 3. B-cell tumors with t(14;19)(q32;q13) can be divided into B-CLL/SLL and DLBCL groups, and the anatomy of IGH::BCL3 in the latter may be different from that of the former.

Alterations in Genome Organization in Lymphoma Cell Nuclei due to the Presence of the t(14;18) Translocation.

Chromosomal rearrangements have been shown to alter genome organization, consequently having an impact on gene expression. Studies on certain types of leukemia have shown that gene expression can be exacerbated by the altered nuclear positioning of fusion genes arising from chromosomal translocations. However, studies on lymphoma have been, so far, very limited. The scope of this study was to explore genome organization in lymphoma cells carrying the t(14;18)(q32;q21) rearrangement known to results in over-expression of the BCL2 gene. In order to achieve this aim, we used fluorescence in situ hybridization to carefully map the positioning of whole chromosome territories and individual genes involved in translocation in the lymphoma-derived cell line Pfeiffer. Our data show that, although there is no obvious alteration in the positioning of the whole chromosome territories, the translocated genes may take the nuclear positioning of either of the wild-type genes. Furthermore, the BCL2 gene was looping out in a proportion of nuclei with the t(14;18) translocation but not in control nuclei without the translocation, indicating that chromosome looping may be an essential mechanism for BCL2 expression in lymphoma cells.

Novel identification of t(14;18)(q32;q21)/IGH::MALT1 in chronic lymphocytic leukaemia.

Chronic lymphocytic leukaemia (CLL) is a clonal B-cell malignancy and remains a chronic disease despite improvements in clinical outcomes since the use of targeted therapies. Both clinical and biological parameters are important for determining prognosis. Unlike other mature B-cell lymphomas, translocations involving the immunoglobulin heavy chain (IGH) locus are uncommon in CLL. There have been few case reports of CLL harbouring t(14;18)/IGH::BCL2 and t(14;19)/IGH::BCL3. Here we describe the first two cases of patients with CLL with documented t(14;18)(q32;q21)/IGH::MALT1. Both cases in this report were associated with lower-risk biological parameters. Thus, FISH testing for MALT1 in cases with unknown IGH translocation partners in the setting of CLL should be implemented in clinical practice to better define such cases.

[Clinical characteristics of 11 patients with chronic lymphocytic leukemia with t (14;19) (q32;q13)].

Objective: To analyze the clinicopathological characteristics of 11 cases of chronic lymphocytic leukemia (CLL) with t (14;19) (q32;q13) . Methods: The case data of 11 patients with CLL with t (14;19) (q32;q13) in the chromosome karyotype analysis results of the Blood Diseases Hospital, Chinese Academy of Medical Sciences from January 1, 2018, to July 30, 2022, were retrospectively analyzed. Results: In all 11 patients, t (14;19) (q32;q13) involved IGH::BCL3 gene rearrangement, and most of them were accompanied by +12 or complex karyotype. An immunophenotypic score of 4-5 was found in 7 patients and 3 in 4 cases. We demonstrated that CLLs with t (14;19) (q32;q13) had a mutational pattern with recurrent mutations in NOTCH1 (3/7), FBXW7 (3/7), and KMT2D (2/7). The very-high-risk, high-risk, intermediate-risk, and low-risk groups consisted of 1, 1, 6, and 3 cases, respectively. Two patients died, 8 survived, and 2 were lost in follow-up. Four patients had disease progression or relapse during treatment. The median time to the first therapy was 1 month. Conclusion: t (14;19) (q32;q13), involving IGH::BCL3 gene rearrangement, is a rare recurrent cytogenetic abnormality in CLL, which is associated with a poor prognosis.

Correlation of t(14;18) translocation breakpoint site with clinical characteristics in follicular lymphoma.

BACKGROUND: t(14;18)(q32;q21) translocation is an important genetic feature of follicular lymphoma resulting in antiapoptotic B-cell lymphoma 2 (BCL2) protein overexpression. On chromosome 18 breakpoint-site variation is high but does not affect BCL2. Breakpoint most commonly occurs at major breakpoint region (MBR) but may happen at minor cluster region (mcr) and between MBR and mcr at 3'MBR and 5'mcr. The aim of this study was to analyze the correlation of t(14;18)(q32;q21) breakpoint site with clinical characteristics in follicular lymphoma. PATIENTS AND METHODS: We included patients diagnosed with follicular lymphoma who received at least 1 cycle of systemic treatment and had the t(14;18)(q32;q21) translocation detected by polymerase chain reaction (PCR) at MBR, mcr or 3'MBR prior to first treatment. Among patients with different breakpoints, sex, age, disease grade, stage, B-symptoms, follicular lymphoma international prognostic index (FLIPI), presence of bulky disease, progression free survival and overall survival were compared. RESULTS: Of 84 patients, 63 had breakpoint at MBR, 17 at mcr and 4 at 3'MBR. At diagnosis, the MBR group had a significantly lower disease stage than the mcr group. Although not significant, in the MBR group we found a higher progression-free survival (PFS) and overall survival (OS), lower grade, age, FLIPI, and less B-symptoms. CONCLUSIONS: Compared to patients with mcr breakpoint, those with MBR breakpoint seem to be characterised by more favourable clinical characteristics. However, a larger study would be required to support our observation.

Investigations of the distant metastatic non-small cell lung cancer without local lymph node involvement: Real world data from a large database.

INTRODUCTION: This study aimed to investigate the presentations and survival outcomes of the distant metastatic non-small cell lung cancer (NSCLC) without lymph node involvement to obtain a clearer picture of this special subgroup of metastatic NSCLC. METHOD: A least absolute shrinkage and selection operator (LASSO) penalized Cox regression analysis was used to select the prognostic variables. A nomogram and corresponding risk-classifying systems were constructed. The C-index and calibration curves were used to evaluate the performance of the model. Overall survival (OS) curves were plotted using the Kaplan-Meier method, and the log-rank test was used to compare OS differences between groups. Propensity score matching (PSM) was performed to reduce bias. RESULT: A total of 12 610 NSCLC patients with M1 category (N0 group: 3045 cases; N1-3 group: 9565 cases) were included. Regarding the N0 group, multivariate analysis demonstrated that age, sex, race, surgery, grade, tumor size, and M category were independent prognostic factors. A nomogram and corresponding risk-classifying systems were formulated. Favorable validation results were obtained from the C-index, calibration curves, and survival comparisons. Survival curves demonstrated that N0 NSCLC patients had better survival than N1-3 NSCLC patients both before and after PSM. Furthermore, the survival of resected N0M1 patients was superior to that of those without surgery. CONCLUSION: In this study, a prognostic nomogram and risk-classifying systems designed for the T1-4N0M1 NSCLC patients showed acceptable performance. Primary lung tumor resection might be a feasible treatment for this population subset. Additionally, we proposed that lymph node stage might have a place in the forthcoming tumor-node-metastasis (TNM) staging proposal for NSCLC patients with M1 category.

Precursory or early lesions of follicular lymphoma: clinical features, pathology, and genetics.

Follicular lymphoma (FL) is an indolent B-cell lymphoma with a germinal center (GC) B cell phenotype that typically harbors t(14;18)(q32;q21). t(14;18) juxtaposes IGH on 14q32 and BCL2 on 18q21, resulting in overexpression of the anti-apoptotic BCL2 protein. However, t(14;18) is also found in the peripheral blood or lymphoid nodes (LNs) of otherwise healthy individuals. Moreover, overt FL has several additional gene alterations involved in epigenetic modification, JAK/STAT signaling, immune modulation, and NF-κB signaling, indicating multi-step lymphomagenesis in FL. There are two early or precursory lesions of FL: t(14;18)-positive cells in the peripheral blood of otherwise healthy individuals and in situ follicular B-cell neoplasm (ISFN). t(14;18)-positive cells are found in 10%-50% of healthy populations, and their incidence and frequency increase with age. The detection of t(14;18) in peripheral blood is a predictive factor for an increased risk of overt FL development. In contrast, ISFN is a histopathologically recognizable precursory lesion, in which t(14;18)-positive cells are confined to the GC of otherwise reactive LNs. ISFN is usually detected incidentally, with an incidence ranging from 2.0% to 3.2%. Occasional ISFN cases have concurrent or metachronous clonally related overt FL or aggressive B-cell lymphoma of a GC phenotype. t(14;18)-positive cells in peripheral blood and isolated ISFN, by themselves, are asymptomatic with limited clinical significance; however, investigations of t(14;18)-positive precursory or early lesions offer meaningful insights into the pathogenesis of FL. This review summarizes the epidemiology, clinical features, pathology, and genetics of precursory or early lesions of FL.

A Novel Bioactive Peptide, T14, Selectively Activates mTORC1 Signalling: Therapeutic Implications for Neurodegeneration and Other Rapamycin-Sensitive Applications.

T14 modulates calcium influx via the α-7 nicotinic acetylcholine receptor to regulate cell growth. Inappropriate triggering of this process has been implicated in Alzheimer's disease (AD) and cancer, whereas T14 blockade has proven therapeutic potential in in vitro, ex vivo and in vivo models of these pathologies. Mammalian target of rapamycin complex 1 (mTORC1) is critical for growth, however its hyperactivation is implicated in AD and cancer. T14 is a product of the longer 30mer-T30. Recent work shows that T30 drives neurite growth in the human SH-SY5Y cell line via the mTOR pathway. Here, we demonstrate that T30 induces an increase in mTORC1 in PC12 cells, and ex vivo rat brain slices containing substantia nigra, but not mTORC2. The increase in mTORC1 by T30 in PC12 cells is attenuated by its blocker, NBP14. Moreover, in post-mortem human midbrain, T14 levels correlate significantly with mTORC1. Silencing mTORC1 reverses the effects of T30 on PC12 cells measured via AChE release in undifferentiated PC12 cells, whilst silencing mTORC2 does not. This suggests that T14 acts selectively via mTORC1. T14 blockade offers a preferable alternative to currently available blockers of mTOR as it would enable selective blockade of mTORC1, thereby reducing side effects associated with generalised mTOR blockade.

GalNAc-T14 may Contribute to Production of Galactose-Deficient Immunoglobulin A1, the Main Autoantigen in IgA Nephropathy.

Introduction: Immunoglobulin A1 (IgA1) with galactose-deficient O-glycans (Gd-IgA1) play a key role in the pathogenesis of IgA nephropathy (IgAN). Mucosal-tissue infections increase IL-6 production and, in patients with IgAN, are often associated with macroscopic hematuria. IgA1-secreting cell lines derived from the circulation of patients with IgAN, compared to those of healthy controls (HCs), produce more IgA1 that has O-glycans with terminal or sialylated N-acetylgalactosamine (GalNAc). GalNAc residues are added to IgA1 hinge region by some of the 20 GalNAc transferases, the O-glycosylation-initiating enzymes. Expression of GALNT2, encoding GalNAc-T2, the main enzyme initiating IgA1 O-glycosylation, is similar in cells derived from patients with IgAN and HCs. In this report, we extend our observations of GALNT14 overexpression in IgA1-producing cell lines from patients with IgAN. Methods: GALNT14 expression was analyzed in peripheral blood mononuclear cells (PBMCs) from patients with IgAN and from HCs. Moreover, the effect of GALNT14 overexpression or knock-down on Gd-IgA1 production in Dakiki cells was assessed. Results: GALNT14 was overexpressed in PBMCs from patients with IgAN. IL-6 increased GALNT14 expression in PBMCs from patients with IgAN and HCs. We used IgA1-producing cell line Dakiki, a previously reported model of Gd-IgA1-producing cells, and showed that overexpression of GalNAc-T14 enhanced galactose deficiency of IgA1, whereas siRNA-mediated GalNAc-T14 knock-down reduced it. GalNAc-T14 was localized in trans-Golgi network, as expected. Conclusions: Overexpression of GALNT14 due to inflammatory signals during mucosal infections may contribute to overproduction of Gd-IgA1 in patients with IgAN.

Expression of integrin ß-7 is epigenetically enhanced in multiple myeloma subgroups with high-risk cytogenetics.

BACKGROUND: Oncogenic overexpression of integrin-ß7 (ITGB7) in cases of high-risk multiple myeloma (MM) was reported to promote enhanced interactions between neoplastic plasma-B cells and stromal cells to develop cell-adhesion mediated drug resistance. METHODS: Expression profiles of adhesion related genes were analyzed in a cohort of MM patients containing major IgH translocations or hyperdiploidies (HY), diagnosed at the premalignant monoclonal gammopathy of undetermined significance (MGUS; n = 103), smoldering multiple myeloma; (SMM; n = 190) or MM (MM; n = 53) stage. Differential expression was integrated with loci-specific alterations in DNA-methylation and chromatin marks in MM patients. A CRISPR-based targeted induction of DNA-methylation at the ITGB7 super-enhancer (SE) in MM.1S cells was employed to intersect the impact of cis-regulatory elements on ITGB7 expression. RESULTS: ITGB7 was significantly (p < 0.05) upregulated in patients with t(14;16) and t(14;20) subgroups in all MGUS, SMM and MM stages, but sporadically upregulated in t(4;14) subgroup at the MM stage. We demonstrate a predetermined enhancer state on ITGB7 in primary-B cells that is maintained under bivalent chromatin, which undergoes a process of chromatin-state alterations and develops into an active enhancer in cases of the t(4;14) subgroup or SE in cases of the t(14;16) subgroup. We also demonstrate that while targeted induction of DNA-methylation at the ITGB7-SE further upregulated the gene, inhibition of ITGB7-SE-associated transcription factor bromodomain-4 downregulated expression of the gene. CONCLUSIONS: Our findings suggest an epigenetic regulation of oncogenic overexpression of ITGB7 in MM cells, which could be critical in MM progression and an attractive therapeutic target.

Paediatric quality-of-life following adenotonsillectomy: an evaluation of T14 paediatric throat disorder quality-of-life outcomes according to operative indication.

INTRODUCTION: Adenotonsillectomy is the most common surgical intervention for obstructive sleep apnoea (OSA) or recurrent tonsillitis. The Paediatric Throat Disorder Quality of Life Outcome (T14) questionnaire is a validated tool completed by parents to compare the outcome of surgery by measuring the pre- and postoperative scores. This study was undertaken to evaluate the quality-of-life outcome in children undergoing surgical intervention for recurrent tonsillitis and/or OSA. METHODS: This was a prospective, uncontrolled study of 117 children who underwent adenotonsillectomy and tonsillectomy at a single tertiary ear, nose and throat department. An analysis of pre- and postoperative T14 paediatric throat disorder quality-of-life outcomes was undertaken at 12 months. RESULTS: Of the 117 children, 105 were included in the study sample; 75 with recurrent tonsillitis, 8 with OSA and 22 with both tonsillitis and OSA. All children had an improved T14 score postoperatively. The greatest change in pre- and postoperative T14 score was observed in the tonsillitis and OSA combined group (mean change -29.36, p<0.001). However, an improvement in T14 score was also noted in the tonsilitis (-24.453, p<0.001) and OSA groups (-14.25, p<0.001). CONCLUSIONS: This study found a statistically significant improvement in the T14 quality-of-life score at 12 months postoperatively in children undergoing adenotonsillectomy. This demonstrates improved parental perception of their child's symptoms for all operative indications of adenotonsillectomy.

Antagonising a novel toxin "T14" in Alzheimer's disease: Comparison of receptor blocker versus antibody effects in vitro.

A 14mer peptide, T14, is a possible signaling molecule driving neurodegeneration. Its levels are doubled in the Alzheimer brain, but its effects can be blocked at the target alpha-7 receptor by a cyclised variant, 'NBP14', which has beneficial effects, in a transgenic mouse model, on the behavioral and histochemical profile. Since the antagonism of T14 has evident therapeutic potential, we explore here an alternative method of preventing its action by comparing the efficacy of NBP14 with a proprietorial polyclonal antibody against T14, 'Ab-19', at inhibiting three distinct effects of the peptide in PC12 cells: calcium influx, cell viability and compensatory acetylcholinesterase (AChE) release. None of these three parameters was affected by either blocking agent when applied alone. However, both NBP14 and the Ab-19 exhibited a dose-dependent profile against the actions of T14 in all three scenarios: the least sensitive effect observed was in the lower dose range, for both the antibody and the receptor blocker, in antagonizing T14-triggered release of AChE: this parameter is interpreted as indirect compensation for the T14-induced compromise of cell viability, triggered by the enhanced influx of calcium through the initial binding of the peptide to an allosteric site on the alpha-7 receptor. As such, it is the most delayed and indirect index of T14 action and thus the least relatively impacted by lowest doses of either NBP14 or Ab-19. In all three scenarios however the effects of T14 are successfully offset by either agent and thus offer two potentially very different therapies against Alzheimer's disease.

Clinical characteristics of 11 patients with chronic lymphocytic leukemia with t (14;19) (q32;q13) / 中华血液学杂志

Objective: To analyze the clinicopathological characteristics of 11 cases of chronic lymphocytic leukemia (CLL) with t (14;19) (q32;q13) . Methods: The case data of 11 patients with CLL with t (14;19) (q32;q13) in the chromosome karyotype analysis results of the Blood Diseases Hospital, Chinese Academy of Medical Sciences from January 1, 2018, to July 30, 2022, were retrospectively analyzed. Results: In all 11 patients, t (14;19) (q32;q13) involved IGH::BCL3 gene rearrangement, and most of them were accompanied by +12 or complex karyotype. An immunophenotypic score of 4-5 was found in 7 patients and 3 in 4 cases. We demonstrated that CLLs with t (14;19) (q32;q13) had a mutational pattern with recurrent mutations in NOTCH1 (3/7), FBXW7 (3/7), and KMT2D (2/7). The very-high-risk, high-risk, intermediate-risk, and low-risk groups consisted of 1, 1, 6, and 3 cases, respectively. Two patients died, 8 survived, and 2 were lost in follow-up. Four patients had disease progression or relapse during treatment. The median time to the first therapy was 1 month. Conclusion: t (14;19) (q32;q13), involving IGH::BCL3 gene rearrangement, is a rare recurrent cytogenetic abnormality in CLL, which is associated with a poor prognosis.

Characterization of a Bioactive Peptide T14 in the Human and Rodent Substantia Nigra: Implications for Neurodegenerative Disease.

The substantia nigra is generally considered to show significant cell loss not only in Parkinson's but also in Alzheimer's disease, conditions that share several neuropathological traits. An interesting feature of this nucleus is that the pars compacta dopaminergic neurons contain acetylcholinesterase (AChE). Independent of its enzymatic role, this protein is released from pars reticulata dendrites, with effects that have been observed in vitro, ex vivo and in vivo. The part of the molecule responsible for these actions has been identified as a 14-mer peptide, T14, cleaved from the AChE C-terminus and acting at an allosteric site on alpha-7 nicotinic receptors, with consequences implicated in neurodegeneration. Here, we show that free T14 is co-localized with tyrosine hydroxylase in rodent pars compacta neurons. In brains with Alzheimer's pathology, the T14 immunoreactivity in these neurons increases in density as their number decreases with the progression of the disease. To explore the functional implications of raised T14 levels in the substantia nigra, the effect of exogenous peptide on electrically evoked neuronal activation was tested in rat brain slices using optical imaging with a voltage-sensitive dye (Di-4-ANEPPS). A significant reduction in the activation response was observed; this was blocked by the cyclized variant of T14, NBP14. In contrast, no such effect of the peptide was seen in the striatum, a region lacking the T14 target, alpha-7 receptors. These findings add to the accumulating evidence that T14 is a key signaling molecule in neurodegenerative disorders and that its antagonist NBP14 has therapeutic potential.

Association between TP73 G4C14-A4T14 polymorphism and different cancer types: an updated meta-analysis of 55 case-control studies.

OBJECTIVE: The TP73 G4C14-A4T14 variant has been associated with elevated cancer risk, but the evidence is inconclusive. We performed a meta-analysis to clarify the role of this variant in cancer development. METHODS: Eligible literature was selected by searching PubMed, Google Scholar, Cochrane Library, and Embase. The meta-analysis was performed using Review Manager 5.4. RESULTS: A meta-analysis of 55 case-control studies showed that the G4C14-A4T14 variant was significantly associated with overall cancer development in five genetic models, including the allele model (AM), codominant model 1 (COD1), COD2, dominant model (DM), and over-dominant model (OD). Sub-group analysis based on ethnicity showed significantly higher risks in Africans in COD2 and RM and in Whites in AM, COD2, DM, and recessive model (RM). Cancer-specific subgroup analysis identified significant risks of gynecological (ovarian, cervical, and endometrial cancer), colorectal, oral, head and neck, and other cancers. Moreover, hospital-based controls revealed significant cancer risks in the AM, COD1, COD2, DM, and RM genetic models. Our findings were confirmed by trial sequential analysis. CONCLUSION: This meta-analysis confirmed that TP73 G4C14-A4T14 significantly elevates the overall cancer risk, especially in White, African, and hospital-based populations, and specifically predisposes individuals to gynecological, colorectal, oral, and head and neck cancers.This meta-analysis was registered at INPLASY (registration number: INPLASY202210070).

When a trophic process turns toxic: Alzheimer's disease as an aberrant recapitulation of a developmental mechanism.

Here we review the idea that Alzheimer's disease (AD) results from aberrant activation of a normal developmental mechanism. This process operates in primarily vulnerable, subcortical nuclei with a distinguishing embryological provenance: the basal rather than the alar plate. All cells are dependent for growth on calcium influx yet these neurons retain a sensitivity to trophic factors into maturity. However, as the brain matures this action becomes detrimental such that the trophic process could turn toxic if triggered in adult brain, in retaliation to an initial insult. The signalling molecule driving this trophic-toxic mechanism is a 14mer peptide (T14) that acts on the alpha-7 receptor to enhance calcium entry, inducing excitotoxicity and proliferation of the receptor, perpetuating a feedforward cycle of neurodegeneration including production of beta-amyloid and p-tau. The T14 system has been previously unrecognised as a basic biological process, yet its pharmaceutical manipulation could have valuable clinical applications.

Multiple myeloma with high-risk cytogenetics and its treatment approach.

Despite substantial advances in anti-myeloma treatments, early recurrence and death remain an issue in certain subpopulations. Cytogenetic abnormalities (CAs) are the most widely accepted predictors for poor prognosis in multiple myeloma (MM), such as t(4;14), t(14;16), t(14;20), gain/amp(1q21), del(1p), and del(17p). Co-existing high-risk CAs (HRCAs) tend to be associated with an even worse prognosis. Achievement of sustained minimal residual disease (MRD)-negativity has recently emerged as a surrogate for longer survival, regardless of cytogenetic risk. Information from newer clinical trials suggests that extended intensified treatment can help achieve MRD-negativity in patients with HRCAs, which may lead to improved outcomes. Therapy should be considered to include a 3- or 4-drug induction regimen (PI/IMiD/Dex or PI/IMiD/Dex/anti-CD38 antibody), auto-transplantation, and consolidation/maintenance with lenalidomide ± a PI. Results from ongoing clinical trials for enriched high-risk populations will reveal the precise efficacy of the investigated regimens. Genetic abnormalities of MM cells are intrinsic critical factors determining tumor characteristics, which reflect the natural course and drug sensitivity of the disease. This paper reviews the clinicopathological features of genomic abnormalities related to adverse prognosis, focusing on HRCAs that are the most relevant in clinical practice, and outline current optimal therapeutic approaches for newly diagnosed MM with HRCAs.