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Purpose: This work aimed to evaluate the impact of a guaranteed access program to imatinib on the survival of patients with Chronic Myeloid Leukemia., Methods: We carried out a retrospective, observational, and analytical study of the database of patients diagnosed with Chronic Myeloid Leukemia of the Instituto Nacional de Cancerología and the Hospital General de México Dr. Eduardo to assess overall survival based on guaranteed access or not to imatinib., Results: With an average follow-up of 99 months, all patients' estimated 20-year overall survival was 72% (95% CI, 76-67). A significant difference was found in the 20-year survival probability in favor of patients with guaranteed access 76% (95% CI, 81-71) vs. 61% (95% CI, 69-52) (p < 0.001), in addition to those in which they had better attachment 81.2% (95% CI, 85-76) vs. 44.9% (95% CI, 52-37) (p < 0.001)., Conclusion: CML is the most frequent chronic leukemia in Mexico. It mainly affects the economically active population (mean age 40), and the prognosis in our country has improved, emulating developed countries; however, the results depend on access to treatment and proper monitoring., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Lymphoedema is caused by an imbalance between fluid production and transport by the lymphatic system. This imbalance can be either caused by reduced transport capacity of the lymphatic system or too much fluid production and leads to swelling associated with tissue changes (skin thickening, fat deposition). Its main common complication is the increased risk of developing cellulitis/erysipelas in the affected area, which can worsen the lymphatic function and can be the cause of raised morbidity of the patient if not treated correctly/urgently. The term primary lymphoedema covers a group of rare conditions caused by abnormal functioning and/or development of the lymphatic system. It covers a highly heterogeneous group of conditions. An accurate diagnosis of primary lymphoedema is crucial for the implementation of an optimal treatment plan and management, as well as to reduce the risk of worsening. Patient care is diverse across Europe, and national specialised centres and networks are not available everywhere. The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN) gathers the best expertise in Europe and provide accessible cross-border healthcare to patients with rare vascular diseases. There are six different working groups in VASCERN, which focus on arterial diseases, hereditary haemorrhagic telangiectasia, neurovascular diseases, lymphoedema and vascular anomalies. The working group Paediatric and Primary Lymphedema (PPL WG) gathers and shares knowledge and expertise in the diagnosis and management of adults and children with primary and paediatric lymphoedema. The members of PPL WG have worked together to produce this opinion statement reflecting strategies on how to approach patients with primary and paediatric lymphoedema. The objective of this patient pathway is to improve patient care by reducing the time to diagnosis, define the best management and follow-up strategies and avoid overuse of resources. Therefore, the patient pathway describes the clinical evaluation and investigations that lead to a clinical diagnosis, the genetic testing, differential diagnosis, the management and treatment options and the patient follow up at expert and local centres. Also, the importance of the patient group participation in the PPL WG is discussed., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The presence of signaling-competent G protein-coupled receptors in intracellular compartments is increasingly recognized. Recently, the presence of G i/o protein-coupled melatonin MT 1 receptors in mitochondria has been revealed, in addition to the plasma membrane. Melatonin is highly cell permeant, activating plasma membrane and mitochondrial receptors equally. Here, we present MCS-1145, a melatonin derivative bearing a triphenylphosphonium cation for specific mitochondrial targeting and a photocleavable o-nitrobenzyl group releasing melatonin upon illumination. MCS-1145 displayed low affinity for MT 1 and MT 2 but spontaneously accumulated in mitochondria, where it was resistant to washout. Uncaged MCS-1145 and exogenous melatonin recruited β-arrestin 2 to MT 1 in mitochondria and inhibited oxygen consumption in mitochondria isolated from HEK293 cells only when expressing MT 1 and from mouse cerebellum of WT mice but not from MT 1 -knockout mice. Overall, we developed the first mitochondria-targeted photoactivatable melatonin ligand and demonstrate that melatonin inhibits mitochondrial respiration through mitochondrial MT 1 receptors., Competing Interests: Declaration of interests The authors declare no competing interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Every time a cell copies its DNA the genetic material is exposed to the acquisition of mutations and genomic alterations that corrupt the information passed on to daughter cells. A tight temporal regulation of DNA replication is necessary to ensure the full copy of the DNA while preventing the appearance of genomic instability. Protein modification by ubiquitin and SUMO constitutes a very complex and versatile system that allows the coordinated control of protein stability, activity and interactome. In chromatin, their action is complemented by the AAA+ ATPase VCP/p97 that recognizes and removes ubiquitylated and SUMOylated factors from specific cellular compartments. The concerted action of the ubiquitin/SUMO system and VCP/p97 determines every step of DNA replication enforcing the ordered activation/inactivation, loading/unloading and stabilization/destabilization of replication factors. Here we analyze the mechanisms used by ubiquitin/SUMO and VCP/p97 to establish molecular timers throughout DNA replication and their relevance in maintaining genome stability. We propose that these PTMs are the main molecular watch of DNA replication from origin recognition to replisome disassembly., Competing Interests: Conflict of Interest The authors declare no conflict of interest., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Melatonin is a neurohormone released in a circadian manner with peak levels at night. Melatonin mediates its effects mainly through G protein-coupled MT 1 and MT 2 receptors. Drugs acting on melatonin receptors are indicated for circadian rhythm- and sleep-related disorders. Tools to study the activation of these receptors with high temporal resolution are lacking. Here, we synthesized a family of light-activatable caged compounds by attaching o -nitrobenzyl ( o- NB) or coumarin photocleavable groups to melatonin indolic nitrogen. All caged compounds showed the expected decrease in binding affinity for MT 1 and MT 2 . The o- NB derivative MCS-0382 showed the best uncaging and biological properties, with 250-fold increase in affinity and potency upon illumination. Generation of melatonin from MCS-0382 was further demonstrated by its ability to modulate the excitation of SCN neurons in rat brain slices. MCS-0382 is available to study melatonin effects in a temporally controlled manner in cellular and physiological settings.

The two human melatonin receptors MT 1 and MT 2 , which belong to the G protein-coupled receptor (GPCR) family, are important drug targets with approved indications for circadian rhythm- and sleep-related disorders and major depression. Currently, most of the pharmacological studies were performed using [ 3 H]melatonin and 2-[ 125 I]iodomelatonin (2-[ 125 I]-MLT) radioligands. Recently, NanoLuc-based bioluminescence resonance energy transfer (NanoBRET) monitoring competitive binding between fluorescent tracers and unmodified test compounds has emerged as a sensitive, nonradioactive alternative for quantifying GPCR ligand engagement on the surface of living cells in equilibrium and real time. However, developing such assays for the two melatonin receptors depends on the availability of fluorescent tracers, which has been challenging predominantly owing to their narrow ligand entry channel and small ligand binding pocket. Here, we generated a set of melatonergic fluorescent tracers and used NanoBRET to evaluate their engagement with MT 1 and MT 2 receptors that are genetically fused to an N-terminal luminogenic HiBiT-peptide. We identified several nonselective and subtype-selective tracers. Among the selective tracers, PBI-8238 exhibited high nanomolar affinity to MT 1 , and PBI-8192 exhibited low nanomolar affinity to MT 2 . The pharmacological profiles of both tracers were in good agreement with those obtained with the current standard 2-[ 125 I]-MLT radioligand. Molecular docking and mutagenesis studies suggested the binding mode of PBI-8192 in MT 2 and its selectivity over MT 1 . In conclusion, we describe the development of the first nonradioactive, real-time binding assays for melatonin receptors expressed at the cell surface of living cells that are likely to accelerate drug discovery for melatonin receptors., Competing Interests: The authors declare no competing financial interest., (© 2022 American Chemical Society.)

The AAA + ATPase VCP regulates the extraction of SUMO and ubiquitin-modified DNA replication factors from chromatin. We have previously described that active DNA synthesis is associated with a SUMO-high/ubiquitin-low environment governed by the deubiquitylase USP7. Here, we unveil a functional cooperation between USP7 and VCP in DNA replication, which is conserved from Caenorhabditis elegans to mammals. The role of VCP in chromatin is defined by its cofactor FAF1, which facilitates the extraction of SUMOylated and ubiquitylated proteins that accumulate after the block of DNA replication in the absence of USP7. The inactivation of USP7 and FAF1 is synthetically lethal both in C. elegans and mammalian cells. In addition, USP7 and VCP inhibitors display synergistic toxicity supporting a functional link between deubiquitylation and extraction of chromatin-bound proteins. Our results suggest that USP7 and VCP FAF1 facilitate DNA replication by controlling the balance of SUMO/Ubiquitin-modified DNA replication factors on chromatin., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Tracking moving masses in several degrees of freedom with high precision and large dynamic range is a central aspect in many current and future gravitational physics experiments. Laser interferometers have been established as one of the tools of choice for such measurement schemes. Using sinusoidal phase modulation homodyne interferometry allows a drastic reduction of the complexity of the optical setup, a key limitation of multi-channel interferometry. By shifting the complexity of the setup to the signal processing stage, these methods enable devices with a size and weight not feasible using conventional techniques. In this paper we present the design of a novel sensor topology based on deep frequency modulation interferometry: the self-referenced single-element dual-interferometer (SEDI) inertial sensor, which takes simplification one step further by accommodating two interferometers in one optic. Using a combination of computer models and analytical methods we show that an inertial sensor with sub-picometer precision for frequencies above 10 mHz, in a package of a few cubic inches, seems feasible with our approach. Moreover we show that by combining two of these devices it is possible to reach sub-picometer precision down to 2 mHz. In combination with the given compactness, this makes the SEDI sensor a promising approach for applications in high precision inertial sensing for both next-generation space-based gravity missions employing drag-free control, and ground-based experiments employing inertial isolation systems with optical readout.

Objectives: Diffuse large B-cell lymphoma (DLBCL) is an aggressive heterogeneous lymphoma with standard treatment. However, 30%-40% of patients still fail, so we should know which patients are candidates for alternative therapies. IPI is the main prognostic score but, in the rituximab era, it cannot identify a very high-risk (HR) subset. The MD Anderson Cancer Center reported a score in the prerituximab era exclusively considering tumor-related variables: Tumor Score (TS). We aim to validate TS in the rituximab era and to analyze its current potential role., Methods: From GELTAMO DLBCL registry, we selected those patients homogeneously treated with R-CHOP (n = 1327)., Results: Five-years PFS and OS were 62% and 74%. All variables retained an independent prognostic role in the revised TS (R-TS), identifying four different risk groups, with 5-years PFS of 86%, 71%, 50%, and very HR (28%). With a further categorization of three variables of the original TS (Ann Arbor Stage, LDH and B2M), we generated a new index that allowed an improvement in HR assessment., Conclusions: (a) All variables of the original TS retain an independent prognostic role, and R-TS remains predictive in the rituximab era; (b) R-TS and additional categorization of LDH, B2M, and AA stage (enhanced TS) increased the ability to identify HR subsets., (© 2019 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

The International Prognostic Index (IPI) is the most widely used score for non-Hodgkin lymphoma but lacks the ability to identify a high-risk population in diffuse large B-cell lymphoma (DLBCL). Low absolute lymphocyte count and high monocytes have proved to be unfavourable factors. Red-cell distribution width (RDW) has been associated with inflammation and beta-2 microglobulin (B2M) with tumour load. The retrospective study included 992 patients with DLBCL treated with R-CHOP. In the multivariate analysis, age, Eastern Cooperative Oncology Group performance status (ECOG-PS), stage, bulky mass, B2M, RDW, and lymphocyte/monocyte ratio (LMR) were independently related to progression-free survival (PFS). A new prognosis score was generated with these variables including age categorized into three groups (0, 1, 2 points); ECOG ≥ 3-4 with two; stage III/IV, bulky mass, high B2M, LMR < 2·25 and RDW > 0·96 with one each; for a maximum of 9. This score could improve the discrimination of a very high-risk subgroup with five-year PFS and overall survival (OS) of 19% and 24% versus 45% and 59% of R (revised)-IPI respectively. This score also showed greater predictive ability than IPI. A new score is presented including complete blood cell count variables and B2M, which are readily available in real-life practice without additional tests. Compared to R-IPI, it shows a more precise high-risk assessment and risk discrimination for both PFS and OS., (© 2019 British Society for Haematology and John Wiley & Sons Ltd.)

The aim of this study is to explore the expression of osteopontin (OPN) and its relationship with prognostic factors and survival in diffuse large B cell lymphoma (DLBCL). A tissue microarray was performed for immunohistochemical evaluation. Contingency tables were analyzed for trends; chi-square test was used to determine differences between groups. Univariate and multivariate Cox proportional hazards-regression analyses were performed to evaluate the impact of prognostic factors on survival. Expression of OPN was observed in 28%. It was different in non-germinal center DLBCL (P=0.04). The mean overall survival (OS) was lower in patients with positive OPN expression (19.762; CI 95% 14.269-25.255) it was not significant (P=0.123). It is not possible to establish a clear relationship between the expression by immunohistochemistry of osteopontin and a poor prognosis but it would be important to complement the analysis with other techniques as PCR or NGS that allow us to assess the influence of the isoforms and post-translational modifications of OPN on the biological behavior of DLBCL. Our findings indicate that OPN expression could be associated with a more aggressive variant of lymphoma: non-germinal center DLBCL., Competing Interests: Conflict of interest: the authors declare no conflict of interest., (©Copyright: the Author(s), 2019.)

The Laser Interferometer Space Antenna (LISA) and its metrology chain have to fulfill stringent performance requirements to enable the space-based detection of gravitational waves. This implies the necessity of performance verification methods. In particular, the extraction of the interferometric phase, implemented by a phasemeter, needs to be probed for linearity and phase noise contributions. This Letter reports on a hexagonal quasimonolithic optical bench implementing a three-signal test for this purpose. Its characterization as sufficiently stable down to picometer levels is presented as well as its usage for a benchmark phasemeter performance measurement under LISA conditions. These results make it a candidate for the core of a LISA metrology verification facility.

The Grupo Español de Linfomas y Trasplantes de Médula Ósea International Prognostic Index (GELTAMO-IPI) stratifies four risk groups in diffuse large B cell lymphoma (DLBCL) patients treated with immunochaemotherapy: low (LR), low-intermediate (LIR), high-intermediate (HIR), and high (HR). The present study explores the effect of GELTAMO-IPI in the DLBCL subtypes defined by the immunohistochaemistry-based Hans algorithm, Germinal Centre B (GCB) and non-GCB. A multivariate Cox regression model including GELTAMO-IPI risk groups, cell of origin (COO) subtypes and their product was developed to evaluate interaction between the two variables. The COO subtype was available in 839 patients (380 GCB; 459 non-GCB) and both the GELTAMO-IPI and the COO subtype in 780 (353 GCB; 427 non-GCB). There were no differences in 5-year overall survival (OS) between the two subtypes. The Cox model revealed interaction between the GELTAMO-IPI risk groups and the COO subtypes (P = 0·005), indicating that GELTAMO-IPI has a different effect in the two subtypes. Three risk groups were stratified in both COO subtypes: in the GCB subtype, LR, LIR and the combined HIR+HR had 5-year OS of 100%, 75% and 52%, respectively. In the non-GCB subtype, LR, the combined LIR+HIR and HR had a 5-year OS of, 97%, 82% and 35% respectively. GELTAMO-IPI identifies a genuine poor outcome group of patients in the DLBCL non-GCB subtype., (© 2018 British Society for Haematology and John Wiley & Sons Ltd.)

Quadrant photodiodes (QPDs) are used in laser interferometry systems to simultaneously detect longitudinal displacement of test masses and angular misalignment between the two interfering beams. The latter is achieved by means of the differential wavefront sensing (DWS) technique, which provides ultra-high precision for measuring angular displacements. We have developed a setup to obtain the spatially resolved response of QPDs that, together with an extension of the simulation software IfoCAD, allows us to use the measured response in simulations and accurately predict the desired longitudinal and DWS phase observables. Three different commercial off-the-shelf QPD candidates for space-based interferometry were characterized. The measured response of one QPD was used in optical simulations. Nonuniformities in the response of the device and crosstalk between segments do not introduce significant variations in the longitudinal and DWS measurands with respect to the standard case when a uniform QPD without crosstalk is used.

The use of mechanical staplers in general surgery and in particularity in biliopancreatic diversion (BPD) has led to a marked reduction in the duration of surgery, thus requiring shorter anesthesia times. In obese subjects this also serves to reduce the risks related to their particular clinical and metabolic conditions. The authors report their experience in 53 patients; in 26 cases automatic linear staplers were used to create the ileal-duodenal and gastric tomy only, whereas the entero-entero anastomosis and gastro-entero anastomosis were performed manually using a biliopancreatic diversion technique. In the remaining 27 cases the operation was performed exclusively using automatic staplers. The paper then examines the complications arising from the use of mechanical staplers, dividing them into early and late. Among the first were two episodes of GEA hemorrhage (7.4%) and an asymptomatic fistula again of the GEA (3.7%). The late complications only included two stenoses (7.4%) of the GEA, both resolved using endoscopic pneumatic dilation.

The authors report their experience in the care of severely obese patients undergoing biliopancreatic diversion (BPD) surgery. The success of this surgical technique not only depends on its correct application but also on correct postoperative management, both immediately and over time. After a short summary of the methods of management used immediately after surgery, the authors focus in greater detail on the most frequent complications in this type of surgery: these are divided into early and late. Among the former, the authors discuss thromboembolic disease, the most severe complications and bronchopneumonia disorders. The authors illustrate the methods of treating both as well as therapies for their prevention. The most frequent and potentially dangerous late complications are examined in detail: protein malnutrition, sideropenic anemia and diarrhea. Lastly, the authors underline the need for a constant rather than episodic approach to the problem of severe obesity since, in their opinion, only continuous and long term application ensures the best results with the fewest complications.

One of the most important problems linked to the conservative surgery of breast cancer consists of local recurrences (LR), even if it has now been proven that the appearance of LR has no influence on overall survival of the patients operated for breast cancer. We have considered 108 patients suffering from breast cancer and treated with quadrantectomy plus axillary dissection. In these patients were found 4 LR (3.7%), that in two cases appeared in the residual mammary gland and in other two cases were found on the skin scar. The mean time of occurrence of the LR was of 43 month (range 18-90 month). The authors have correlated the appearance of LR with some characteristics of the tumor, as the pT, the histologic type, the histologic Grading, the estrogen receptor status and the extensive intraductal component of the tumor (EIC). No particular correlations were found between the pT, histologic type, histologic Grading, estrogen receptor status of the tumor and the onset of LR. Instead a significant correlation was found between the LR appearance and the EIC of the tumor. In fact, for the tumors with a rich EIC there was found a 11.5% incidence of LR against a 1.2% impact of LR for the tumors with a low EIC. The authors conclude that is impossible now to assert that exist really some prognostic factor but is most important to note that there are many data in the literature that seems ever more to point at the rich EIC of the tumor as an important prognostic factor of LR.

Following a description of the most common galactographic semeiotics in relation to the different types of secretion, the Authors report their personal experience in the use of galactography to diagnose breast cancer. Histopathological tests revealed the presence of carcinoma in 14 (29.2%) out of a total 48 galactographic examinations. In conclusion, the Authors underline the high degree of diagnostic precision of galactography, a test which contributes to the identification of a considerable number of carcinomas during the preclinical stage.

The authors confirm the actuality and validity of decompressive cecostomy in emergency treatment of large bowel obstructions. Taking into account that staplers have substantially reduced the rate of complications and inconvenient of gastrointestinal surgery, their use of cecostomy closure is proposed. Advantages obtained with this technique, namely lack of infections and incisional hernias, are underlined.