Gutta-percha points and root canal sealers have been used for decades in endodontics for root canal obturation. With techniques such as single cone methods, the amount of sealer is larger, making their properties more critical. However, relatively few reports have comprehensively evaluated their biological effects. To this end, we evaluated three types of sealers, zinc oxide-fatty acid-, bio-glass- and methacrylate resin-containing sealers were considered. Their biological effects were evaluated using a rat subcutaneous implantation model. Each sealer was loaded inside a Teflon tube and implanted subcutaneously in the backs of rats. Inflammatory cells were observed around all samples 7 days after implantation and reduced after 28 days. Our results revealed that all samples were in contact with the subcutaneous tissue surrounding the sealer. Additionally, Ca and P accumulation was observed in only the bio-glass-containing sealer. Furthermore, each of the three sealers exhibited unique immune and inflammatory modulatory effects. In particular, bio-glass and methacrylate resin sealers were found to induce variable gene expression in adjacent subcutaneous tissues related to angiogenesis, wound healing, muscle tissue, and surrounding subcutaneous tissue. These results may help to understand the biological impacts of root canal sealers on surrounding biological tissues, guiding future research and comparisons with new generations of materials.  In endodontic treatments, various types of sealers for root canal obturation (RCO) are clinically applied along with gutta-percha (GP) points ,2. AfterCold lateral filling and warm vertical condensation methods using a combination of GP points and RCO sealers are frequently used filling strategies  and haveVarious types of RCO sealers have been developed over the last decades, the widely used being calcium-hydroxide-based and resin-based sealers, as well as zinc oxide sealers based on fatty acids . Zinc oxRoot canal sealers come in contact with periapical tissues following the filling procedure. However, the biological effects of root canal sealers developed using various concepts and different main components are not completely clear. Specifically, a comprehensive analysis of the genes regulated by each root canal sealer has not been conducted. Therefore, the purpose of this study was to evaluate three types of commercially available sealers, i.e., zinc oxide-fatty acid-, methacrylate resin-, and bio-glass-containing sealers using a rat model. These materials were chosen since they are the most frequently used in the country where the project was conducted (Japan). The null hypothesis was that there is no difference in gene expression related to wound healing regulation and biocompatibility in tissues in which the three different root canal sealers evaluated were implanted.All surgeries were performed under general anesthesia, and all efforts were taken to minimize pain or discomfort. This study was approved by the Ethical Guidelines Committee for Animal Care of Osaka University Graduate School of Dentistry (No. 29-028-0).® as the zinc oxide-fatty acid sealer; Nishka Canal Sealer BG®  as the bio-glass-containing sealer; Metaseal soft paste®  as the methacrylate resin sealer. The components of the RCO sealer used in this study are presented in The following RCO sealers were obtained: Nishka Canal Sealer NFourteen 9-week-old Wistar rats weighing 200–230 g  were used for the in vivo experiments. Before material implantation, anesthesia was induced with 0.3 mg/kg medetomidine hydrochloride , 4.0 mg/kg midazolam , and 5.0 mg/kg butorphanol . Body hair was then partially removed from the back of the rat where material implantation was planned. Careful dissection was performed and a 10 mm incision line was established B, parallThe subcutaneously implanted cylinders were retrieved after 7 and 28 days. The collected specimens were fixed in 4% paraformaldehyde at 4 °C for 24 h and then embedded in paraffin. After paraffin embedding, the tubes were removed, serial sections of longitudinal cross-sections (6 µm thick) were prepared, and hematoxylin and eosin (HE) staining was applied.The RCO sealer-filled cylinders were subcutaneously implanted, and after 14 days, the entire subcutaneous tissue around the specimen was harvested. Paraformaldehyde (2%) and glutaraldehyde (2.5%) were used for fixation. Postfixation was performed in 2% osmium tetroxide. Tissue specimens were dehydrated in ascending ethanol series and embedded in epoxy resin . The surfaces of each specimen were polished well with diamond abrasive sheets . Backscattered electron images were acquired using SEM .Rats with each root canal material implanted subcutaneously were kept for 14 days, and elemental analysis of the neighboring subcutaneous tissue affected by the RCO sealer was performed via micro-X-ray fluorescence spectroscopy (micro-XRF), based on previous reports . ImplantComprehensive gene expression analysis of biological tissues via RNA-seq was performed 10 days after subcutaneous implantation of the RCO sealers, based on previous reports . The anip-values. To classify the DEGs into Gene Ontology (GO) terms, we uploaded DEGs to the online DAVID Bioinformatics Resources website (PMID: 17576678). The results of the gene ontology analysis were visualized with the number of genes and adjusted To histologically evaluate the effect of the RCO sealer on the subcutaneous tissues, they were removed 7 and 28 days after implantation A. As a cSubcutaneously implanted RCO sealer-filled cylinders and the surrounding tissue were collected after 14 days for microstructural observation via SEM . Soft tiA representative image of the Metaseal soft paste group is shown in In other groups, the distribution of elements was comparable to that detected as background in the subcutaneous tissue and was not observed. A heatmap showing the clustering of the top 10,000 genes contributing to the differences in each RCO sealer group showed that the Canal Sealer N group showed a gene expression pattern relatively similar to the control. In contrast, the Metaseal soft paste and the Canal Sealer BG groups showed different gene expression patterns A. These Venn diagrams were drawn to represent genes with increased  or decreRegarding upregulated genes , the CanAs regards the function of genes whose expression was suppressed, the downregulation of genes related to inflammatory responses was common to both materials  compared to control. The Metaseal soft paste group also showed downregulation of the genes related to the suppression of inflammation, which was different from the Canal Sealer BG group. A three-way Venn diagram illustrates overlapping of downregulated genes between groups. The top six unique GO terms are listed in each section.Transcriptome (RNA-seq) data are reported in detail in Zinc oxide-eugenol sealers were developed in the 1930s and have long played a central role in endodontic RCO ,18. HoweIn addition, many RCO sealers, such as salicylic acid-based, silicone-based, glass ionomer-based, tricalcium silicate-based (MTA/bioceramic), methacrylate resin-based, and epoxy resin-based sealers have been developed and are widely used worldwide, with each dental company making improvements that can be applied in endodontic treatment . In the There have been many in vitro and in vivo reports evaluating many root canal filler sealers, focusing on their sealing and antibacterial properties, which can cause endodontic failures, as well as their cytotoxicity, which is related to their biocompatibility ,22,23,24In endodontics, RCO is an important procedure that intends to maintain sterile conditions in root canals in the long term and thereby maintain the results achieved by the disinfection and root-canal shaping procedure. RCO sealers are considered biomaterials since they interact with biological tissues for a medical purpose. These materials are sometimes referred to as “bioactive,” although this terminology is actually a misuse of the term in all commercially available materials today . HoweverParadoxically, relatively few studies extensively investigating the biological effects of RCO sealers are available. In particular, there were no reports including a comprehensive genetic analysis. In this study, we evaluated the biological effects of three types of root canal filler sealers , for which little information was available.Histological evaluation via HE staining showed an inflammatory reaction in all samples 7 days after treatment . HoweverAngiogenesis was also observed in the subcutaneous implantation model. These results were supported by RNA-seq results, which confirmed that Canal Sealer BG predominantly increased the expression of genes related to wound healing and angiogenesis . MetaseaThe results of this comprehensive genetic analysis showed that the control and Canal Sealer N had a limited effect on gene expression in the subcutaneous tissue compared to the other sealers. A heatmap showing the clustering of the top 10,000 genes contributing to the differences between each RCO sealer group showed that the Canal Sealer N group showed a gene expression pattern that was similar to that of the control, while Metaseal soft paste and Canal Sealer BG showed different gene expression patterns between groups. Although the clustering was material-specific, the technical error of the gene analysis in this study was considered to be small.Additionally, the results of RNA-seq showed that several genes were predominantly upregulated  and seveThe methacrylate resin sealer used this study, Metaseal soft paste, is a highly biocompatible sealer , and theIn the present study, three available RCO sealers developed based on their respective concepts were evaluated in detail. This is the first report to examine the comprehensive gene expression profile in tissues affected by RCO sealers. The results provide not only basic data for collecting the biological effects of currently available RCO sealers, but also for the development of next-generation RCO sealers with bioactive effects. RNA-seq metadata is publicly available on DDBJ and can be used by researchers worldwide. Although a systematic review indicated that the available evidence does not indicate that the material used for RCO has any effect on periapical healing , it is cAs a limitation of this study, a subcutaneous implantation model was used to investigate the biological effects of RCO sealers , which dThe zinc oxide-fatty acid, bio-glass-containing and methacrylate resin sealer used in this study all have high biocompatibility without inducing excessive inflammatory responses. The bio-glass and methacrylate resin sealer groups were found to have variable gene expression in adjacent subcutaneous tissues related to angiogenesis, wound healing, and muscle tissue, the tissue surrounding subcutaneous tissue. In contrast, the eugenol-based sealer group showed a relatively similar gene expression pattern to the control. The present work may help to understand the biological effects of root canal sealers on surrounding biological tissues, which will guide their future developments and help compare them with new generations of materials.


We report a rare case of paraneoplastic bullous pemphigoid associated with mantle cell lymphoma.The patient presented with 5 months’ history of generalized skin itchiness, night sweat and loss of weight. The skin manifestations started over the foot and hand area. However, he started to developed tense blisters over the face, trunk and limbs 3 days prior to this admission.The skin biopsy report showed subepidermal bullae, in which the immunofluorescence findings in keeping with bullous pemphigoid. The peripheral blood immunophenotyping was suggestive of mantle cell lymphoma. Hence, a diagnosis of paraneoplastic bullous pemphigoid associated with mantle cell lymphoma was made.The patient was initiated with a cytoreduction chemotherapy.Unfortunately, patient’s condition deteriorated further due to neutropenic sepsis and he succumbed after 2 weeks of intensive care.Bullous pemphigoid associated with mantle cell lymphoma are very rare. The presentation of bullous pemphigoid led to the detection of mantle cell lymphoma. Early diagnosis and appropriate treatment is crucial in managing this aggressive type of the disease. Both, bullous pemphigoid and mantle cell lymphoma had a parallel clinical course which suggests a paraneoplastic phenomenon in this reported case. Bullous pemphigoid is an autoimmune subepidermal blistering disorder. Mantle cell lymphoma is a B-cell malignancy of a rare type of non-Hodgkin lymphoma. Bullous pemphigoid associated with mantle cell lymphoma is even rarer which may suggest a paraneoplastic phenomenon.A 29-year-old Malay man, a federal plantation supervisor, was admitted with 5 months’ history of generalized skin itchiness, night sweat and loss of weight. The skin itchiness started over the foot and hand area. However, he started to developed tense blisters over the face, trunk and limbs 3 days prior to this admission. He gave history of applying sulfur-based powder solution on the itchy areas for 3 days’ duration prior to the blisters’ eruption. There was no prolonged fever, cough, recurrent oral ulcer, hair loss and joint pain. Family history was insignificant of malignancy or autoimmune disease. He neither had drug nor food allergy. Physical examination revealed multiple scaly and dry erosions on her scalp and crusted erosions on the face and periauricular region. Erosions were evidence on the hard palate and buccal mucosa. Multiple intact tense blisters with crusted erosions were found on the upper limbs, lower limbs, back, and lower abdomen Figs.  and 2. TThe skin biopsy finding showed subepidermal bullae, in which the lumen consists of acantholytic cells and neutrophils, with positive immunofluorescence (IF) to immunoglobulin (Ig)-G, C3, C1q at the dermo-epidermal junction which in keeping with bullous pemphigoid Figs. . There wPatient was started with a cytoreduction chemotherapy regime comprised of rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate and prednisolone. Unfortunately, patient’s condition had deteriorated further due to neutropenic sepsis and patient succumbed after 2 weeks of intensive care.–4Our patient presented with bullous pemphigoid associated with mantle cell lymphoma. Bullous pemphigoid is an autoimmune subepidermal blistering disorder which occurs mainly in the elderly but may rarely present in children and younger adults. It is an acquired autoimmune disease which specifically involved the deposition of IgG and/or C3 along the basement membrane zone on direct IF. Circulating IgG autoantibodies are presence in most patients that can be demonstrated by indirect IF. Different types of malignant diseases can present with bullous pemphigoid, but it is still unclear with regards to the paraneoplastic significance of this association. Production of antibodies to tumor-specific antigens that might cross-react with the basal membrane zone would explain the relationship between carcinoma and bullous pemphigoid. Another theory suggested that secondary production of anti-basement membrane zone antibodies by the tumor cells occurred through secretion of a substance that could damage the basement membrane. Theory of genetic predisposition to both diseases or the possibility that the same external agent might generate the cancer and the basement membrane zone damage was explored. In B-cell neoplasia, the rare occurrence of autoantibody-mediated skin disease has been reported in association with paraneoplastic pemphigus.,7A study showed that 11% of 110 cases of bullous pemphigoid were associated with carcinoma. It is derived from a subset of naive pregerminal center cells that are localized in the mantle zones of secondary follicles or in the primary follicles. Chromosomal translocation t is characteristic of mantle cell lymphoma. Mantle cell lymphoma is commoner among older adults with a median age in their 60s and has a male predominance.,11 Mantle cell lymphoma is diagnosed based on a biopsy of a lymph node, tissue, bone marrow or blood phenotype which shows the typical morphology of monomorphic small to medium sized lymphoid cells with irregular nuclear contours. Small cell, mantle zone, diffuse and blastic are four recognized mantle cell lymphoma cytologic variants. Immunophenotyping for mantle cell lymphoma is commonly positive with CD20, CD5, and cyclin D1 while being negative for CD10 and Bcl6.Mantle cell lymphoma is a B-cell malignancy of a rare type of non-Hodgkin lymphoma. It comprises 3 to 10% of all non-Hodgkin lymphomas. Patients usually present at stage III/IV disease with extensive lymphadenopathy, blood and bone marrow involvement, and splenomegaly, as seen in our patient. Due to advanced stage disease with associated paraneoplasticbullous pemphigoid, the patient was started with cytoreduction regime consist of rituximab plus chemotherapy. Options of treatment include rituximab-fludarabine, cyclophosphamide, rituximab-cyclophosphamide, vincristine, prednisone, rituximab-cyclophosphamide, vincristine, doxorubicin, prednisone, rituximab-bendamustine, and rituximab-chlorambucil. For fit and young patients (<60–65 years with no significant comorbidities), current evidence suggests that optimal treatment is intensive chemotherapy with a view to achievinga complete response prior to autologous peripheral blood stem cell transplantation. Suitable regimens would include rituximab and high-dose cytarabine.Mantle cell lymphoma has an aggressive clinical course with a pattern of resistant and relapsing disease making it incurable to standard therapy with a median survival rate of 4 to 5 years. The previous reported case was a young 39-yearold Caucasian man who presented with severe odynophagia for 3 months resulting in weight loss of 5 kg and extensive eruption of tense blisters and painful oral lesions for 6 weeks. The patient managed to undergo an allogeneic bone marrow transplantation after cytoreduction with 2 courses of fractionated cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and dexamethasone, which were alternated with high-dose methotrexate and cytosine arabinoside after the diagnosis of mantle cell lymphoma stage IVa was established. The bullous pemphigoid lesions gradually disappeared during cytoreduction and remain stable until after 48 months of follow-up, and required no further topical or systemic therapy. In our case, the presentation of bullous pemphigoid led to the detection of mantle cell lymphoma. However, the late presentation at diagnosis and aggressiveness of the disease, patient’s condition had deteriorated after commencing cytoreduction chemotherapy. Both, bullous pemphigoid and mantle cell lymphoma had a parallel clinical course which suggests a paraneoplastic phenomenon in this reported case.Bullous pemphigoid associated with mantle cell lymphoma is very rare with only one case has been reported in the literature.Bullous pemphigoid associated with mantle cell lymphoma are very rare as seen in our case report. The presentation of bullous pemphigoid led to the detection of mantle cell lymphoma. Early detection of the diseases and appropriate multi-discipline team approach is essential in managing this type of the disease.The authors would like to acknowledge Universiti Teknologi MARA (UiTM) Sungai Buloh for supporting the submission of the following article.Writing – original draft: Ahmad Bakhtiar Md Radzi.Writing – review & editing: Sazzli Shahlan Kasim, Ahmad Bakhtiar Md Radzi.


We demonstrated the application of dynamic treatment regimes using the National Diabetes Action Canada Repository in which we applied a collection of mainstream statistical learning algorithms. We generated an ensemble of statistical learning algorithms using the SuperLearner based on the following base learners: (i) least absolute shrinkage and selection operator, (ii) ridge regression, (iii) elastic net, (iv) random forest, (v) gradient boosting machines, (vi) neural network. Each statistical learning algorithm was fitted using the pseudo-population with respect to the marginalization of the time-dependent confounding process. The covariate balance was assessed using the longitudinal (i.e. cumulative-time product) stabilized weights with calibrated restrictions. Our results indicated that the treatment drop-in cohorts  may improve diabetes care provision in relation to treatment naïve cohort. As a clinical utility, we hope that this article will facilitate discussions around the prevention of adverse chronic outcomes associated with diabetes through the improvement of diabetes care provisions in primary care.Although machine learning has permeated many disciplines, the convergence of causal methods and machine learning remains sparse in the existing literature. Our aim was to formulate a marginal structural model in which we envisioned hypothetical  dynamic treatment regimes using a combination of drug therapies to manage diabetes: metformin, sulfonylurea and SGLT-2. We were interested in estimating


The use of computer-aided rapid prototyping (CARP) models was considered to reduce surgical trauma and improve outcomes when autotransplantation of teeth (ATT) became a viable alternative for dental rehabilitation. However, ATT is considered technique-sensitive due to its series of complicated surgical procedures and unfavorable outcomes in complex cases. This study reported a novel autotransplantation technique of a 28-year-old patient with an unrestorable lower first molar (#36) with double roots. Regardless of a large shape deviation, a lower third molar (#38) with a completely single root formation was used as the donor tooth. ATT was performed with a combined use of virtual simulation, CARP model-based rehearsed surgery, and tooth replica-guided surgery. A 3D virtual model of the donor and recipient site was generated from cone-beam computed tomographic (CBCT) radiographs prior to surgery for direct virtual superimposition simulation and CARP model fabrication. The virtual simulation indicated that it was necessary to retain cervical alveolar bone during the surgical socket preparation, and an intensive surgical rehearsal was performed on the CARP models. The donor tooth replica was used during the procedure to guide precise socket preparation and avoid periodontal ligament injury. Without an additional fitting trial and extra-alveolar storage, the donor tooth settled naturally into the recipient socket within 30 s. The transplanted tooth showed excellent stability and received routine root canal treatment three weeks post-surgery, and the one-year follow-up examination verified the PDL healing outcome and normal functioning. Patient was satisfied with the transplanted tooth. This cutting-edge technology combines virtual simulation, digital surgery planning, and guided surgery implementation to ensure predictable and minimally invasive therapy in complex cases. Autotransplantation of teeth (ATT) has emerged as a new alternative for dental rehabilitation, involving use of surgical procedures to replace a deteriorated tooth with a donor tooth transplanted to the recipient site in the same individual ,2,3. TheWith recent advances in 3-dimensional (3D) printing technology in dentistry, the application of computer-aided rapid prototyping (CARP) to create a replica of the donor tooth in ATT has improved outcomes ,7. UsingATT is considered technique-sensitive because of the series of complicated surgical procedures, including minimally invasive tooth extraction, precise socket preparation, and donor tooth replacement ,11. RetaVirtual simulation technology has been widely utilized in pre-clinical education and treatment planning ,13, but A 28-year-old female patient presented to the Department of Endodontics at the Hospital of Stomatology  with the chief concern of a largely destroyed left lower molar. The patient had a history of root canal treatment 5 years earlier. Clinical examination revealed that tooth #36 had extensive caries and pulp polyp, with most of the residual crown below the gingiva. Tooth #38 had erupted partly and showed intact crown structure A,B. A prThe virtual construction of a digital image was created using intra-oral scanning and cone-bean computed tomographic (CBCT) radiographs through surgical planning software . Specifically, a threshold value was utilized to generate a mask to isolate the teeth from the surrounding tissues. The segmented teeth were reconstructed and exported into the stereolithography (STL) file . Donor tThereafter, 3D virtual images of the tentative extraction socket and donor tooth in the software were exported to STL files for fabricating 3D-printed CARP models . The CARP models of the tentative extraction socket C,D and dBefore the surgery, the CARP replica donor tooth was sterilized by high-temperature steam, and the surgical sites were thoroughly cleaned. Autotransplantation of tooth #38 to the extraction socket of tooth #36 was performed under local anesthesia. Minimally traumatic extraction of tooth #36 was first conducted A. The exTo accommodate the donor tooth in an appropriate space, the recipient socket was subsequently prepared with a long-neck round bur, as had occurred during the in vitro surgical rehearsal on the CARP models E. As indSince the transplant bed had been successfully created, donor tooth #38 was extracted atraumatically H. MinimaA postoperative radiograph was taken immediately after autotransplantation. The radiolucent region around the donor tooth resulted from the space discrepancy between double root and single root, as expected A. Tooth ATT has several intriguing advantages compared to other restoration options. Compared with fixed bridge restoration which requires the preparation of adjacent healthy teeth, ATT is a minimally invasive technique for denture defect restoration . With reApart from PDL healing, the optimal success of transplanting the tooth with an immature donor tooth is associated with pulp healing and root formation. Pulp revascularization is possible when the transplanted tooth has immature roots. Favorable PDL healing and pulp healing were statistically significantly associated with the stage of root development. Transplanted teeth with divergent and parallel apical root development exhibited better outcomes than those with convergent roots . It is sVirtual simulation has received much attention in dental education and pre-clinic assessments, such as in implant placement, endodontic microsurgery, orthognathic surgery planning, and virtual prosthetic planning ,20,21. GIn the present case, intra-oral scanning and CBCT radiographs of donor and recipient sites were reconstructed directly into the 3D models in the surgical planning software, where the residual roots of tooth #36 in the recipient site were trimmed out to form a tentative extraction socket A. ComparIt has been well documented that the application of CARP models in ATT contributed to a favorable survival rate compared with conventional ATT . The criDespite the flourishing of 3D printing technology in dentistry, some concerns have also been raised. A significant difference in geometric measurements between the CBCT-generated tooth CARP replicas and the actual tooth was discovered. On average, there was a mean absolute length difference of 0.36 mm and a mean geometric difference of 0.56 mm. Qualitative analysis indicated that the replicas were generally slightly larger in size, which may be beneficial in this clinical context in that the autotransplanted tooth should not be inserted into the recipient site with overpressure . HoweverA donor tooth with a mature root is recommended to complete root canal treatment before or two weeks after surgery . In thisThis study reported a cutting-edge technique in ATT that combines virtual simulation, digital surgery planning, and guided surgery implementation to ensure predictable and minimally invasive therapy in complex cases. Preoperative virtual simulation and in vitro surgery rehearsal on CARP models were performed to predict and practice the actual autotransplantation surgery. The CARP tooth replica was employed as a surgical guide to create the optimal recipient socket. As a result, the donor tooth settled into the recipient site with an intact PDL and good stability, resulting in a successful PDL healing outcome after 1 year. Future randomized controlled studies on the accuracy and outcome of guided ATT surgery on larger sample sizes are needed.


Cancer screening is recommended for select cancers worldwide. Cancer screening has become increasingly effective and accessible and often increases overall survival. However, the mental health effects of cancer screening, such as its impact on depression, anxiety, and post-traumatic stress disorder, are largely unknown. Conflicting available literature indicates the negative, neutral, and positive mental health effects of cancer screening across cancer types. There are a limited number of randomized controlled trials measuring the mental health effects of cancer screening. Overall, the more negative and life-threatening the screening results, the greater the mental health effects. Screening for cancer without a known precursor, for example, due to family history, can have positive impacts such as decreased worry and increased quality of life. However, receiving a cancer diagnosis often has negative mental effects that increase with the life-threatening potential of malignancy. In this study, we review the existing literature and provide recommendations for future research to determine if and when cancer screening is the best practice. The clinical utility of large-scale screening procedures remains controversial.,8–13 While extending survival rates is a clear argument for screening practices, there can be a number of harmful effects of cancer screening, including negative effects on patient mental health.Cancer screening has become an increasingly common practice because of the poor survival rates associated with many cancers. The mental health impact of cancer screening has been a growing conversation, as emerging studies have shown contradictory results regarding the mental impact of screening and have included negative, neutral, or positive impacts on mental health. proposed that screening programs are justifiable when ten conditions are met  in the short (2–3 hours) or moderate (1 month) term. The largest study  on colorectal cancer screening found effects of receiving abnormal results on the Hospital Anxiety and Depression Scale (HADS) and Short-Form Health Related Quality of Life (HRQL) Form or by participating in screening in general. Those with healthy results showed improvements in all the measures.A number of studies have shown that cancer screening has little to no negative impact on mental health in the absence of a known precursor. A systematic review of lung cancer screening found that the effects varied across studies, but in general, any negative effects of screening diminished or resolved at long-term follow up (≥6 months postscreening).Evidence suggests that screening can increase mental distress. A systematic review reported that cancer screening can cause low-to-moderate levels of distress. (n = 102) found no evidence of short-term negative impacts of pancreatic screening on mental health, measured using 2 Likert-scale questions asking about worries about developing pancreatic or other cancers. At the year follow up, regardless of the screening results, participants reported significantly decreased worry about developing cancer. In a study (n = 231) investigating the effects of colonoscopies, 30% of participants reported a clinically significant improvement in the vitality and mental health domains of quality of life at 5 weeks, using the Short-Form Quality of Life Assessment (SF-36).,18Cancer screening can positively impact mental health. O’Neill et alCancer screening may also promote healthy practices among the participants. In a study (n = 187) investigating mental health impacts (state-trait anxiety inventory (STAI), psychological consequences of screening [PCQ], and the HADS) of skin cancer screening (via skin examination), researchers found that screening had no negative impact on mental health 3 months after examination. Further, those who underwent more thorough skin examinations reported better skin cancer prevention methods postexamination and increased the likelihood of recommending exams to peers. Those with more thorough examinations also reported greater satisfaction with the exam.In summary, across different types of cancers, in the absence of a cancer precursor or risk, screening has a range of potential impacts  on mental health. The positive mental health effects of screening are compelling, and alongside the potential for increasing positive patient behaviors, support screening in those without known precursors, given positive results on other endpoints, such as cancer survival. However, the findings should be considered alongside the methodological limitations. Frequently used mental health measures, such as the SF-36 and HADS, may be outdated, as they were created in the 1980s through the early 1990s and use colloquial phrases to assess mental health  as opposed to symptoms correlated with the Diagnostic and Statistical Manual of Mental Health Disorders (DSM). Carefully designed studies with up-to-date measures are needed to fully understand the impact of cancer screening on mental health.Evidence has shown that cancer screening can have a negative impact on mental health. One study (n = 2537) offered low-dose chest CT screening for participants at risk (current or former smokers considered at risk using a risk prediction tool) for developing lung cancer and showed that clinically significant anxiety, as measured using the State-Trait Anxiety Inventory (STAI), increases at 1 year follow up as a result of the screening. No differences in HRQL were found. One study (n = 198) investigated the effects of cancer screening in patients with a family history of pancreatic cancer or BRCA2 mutation. Across 3 months, there was no effect of screening on general/global distress or risk perception, but those with a family history showed decreases in cancer-related worry.High-risk individuals, such as those with a family history of pancreatic cancer, may benefit from cancer screening. The results indicate that intrusive thoughts about cancer decreased significantly over time. Cancer-related worry decreased at 3 months and showed a small, significant increase at 12 months.In a study exploring screening effects of a pancreatic cancer genetic counseling and screening intervention, 129 participants with a familial history of pancreatic cancer or BRCA2 mutation were assessed at baseline and included prescreening and a genetic counseling session, and 3- and 12-month follow-up postscreening.), which increase along with the patient’s level of perceived risk. In a study comparing patients with a family history of pancreatic cancer (n = 378) to those without (n = 1528), those with a family history were more willing to engage in cancer screening than controls.Screening can cause mental distress, as screening for one’s family risk for ovarian cancer (n = 157 women) can cause elevated anxiety (STAI) and depressive symptoms  compared the severity of anxiety and depressive symptoms between individuals diagnosed with precursors to multiple myeloma (MM), monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), individuals newly diagnosed with MM, and individuals in MM treatment. The study did not find a significant difference in anxiety symptoms between groups using the Generalized Anxiety Disorder 7-item scale (GAD-7). However, levels of depressive symptoms  were higher for those in the MM treatment group compared to those newly diagnosed with MGUS. Patients with MGUS report higher physical HRQL  than patients with newly diagnosed MM and treated MM.-37 depression, and post-traumatic stress disorder (PTSD) symptoms,-41 especially shortly after the results are obtained. A meta-analysis found that testing positive for BRCA1/2 is associated with a small increase in anxiety symptoms 1 month after being informed of the results. However, after 1 month, these symptoms subsided to baseline. Those who received results that they were not carriers had a decrease in anxiety symptoms up to a month after the results, which also returned to baseline by the 1-month follow up. Similarly, screening positive for a genetic mutation that causes hereditary nonpolyposis colorectal cancer (HNPCC) syndrome has been shown to cause a small short-term increase in anxiety symptoms that returned to baseline at the 1- and 6-month follow ups.-36Being diagnosed with a precursor or genetic condition that increases the likelihood of cancer development has been associated with higher levels of anxiety, found that women with BRCA1/2 mutations (n = 117) reported significantly higher depressive symptoms  at 1 and 6 months after receiving the results. This pattern was maintained at the long-term follow up, 12 months after the results but was no longer significant. In a study investigating the impact of BRCA1 screening on those with a family history of BRCA1 (n = 287), there were no differences in depressive symptoms (HADS) 6-weeks after the results between those with and without BRCA1 compared to baseline. In this case, a positive BRCA1 result was not associated with an increase in depressive symptoms.Beran et al carriers of BRCA1/2 mutations (n = 65) were more likely to experience symptoms of PTSD (measured via semistructured diagnostic interviews) resulting from the screening experience, compared to noncarriers, 3 to 6 months after being informed about BRCA1/2 status. This study was unique in that it measured psychological effects via semistructured interviews, which is more robust than most studies in this review. However, the sample size was small, only 12 of the participants had BRCA1/2, and only 3 of them developed PTSD symptoms after being informed of their status. Long-term follow-up data were unavailable. In a small qualitative study, patients diagnosed with MGUS (n = 14) reported poor psychological adjustment to their condition, particularly at the time of diagnosis. The participants also reported feelings of isolation, increased uncertainty, and limited psychosocial support.Screening results indicate that cancer precursors can also cause symptoms of post-traumatic stress disorder (PTSD). In a study by Hamann et al,In summary, the mental health effects of receiving positive results of having a cancer precursor or risk factor seem more severe than those of less intensive screening. However, in general, negative effects seem most prominent in the days and weeks after the results and typically subside over time. Interventions such as informing patients of these potential short-term effects and short-term therapy to cope with the results should be investigated as ways to ameliorate these effects. Indeed, women who were screened for breast cancer and reported being satisfied with the social support of their providers throughout the screening process had lower levels of anxiety.-48 In a large multicenter study (n = 2812) of patients with lung cancer, participants receiving false-positive results experienced no significant differences in anxiety or quality of life (STAI and HRQL) at 1 or 6 months posttest , compared to those with a negative result. A meta-analysis of false-positive mammography results found that females with false positives were not more likely to experience depressive symptoms than those with normal results.The effects of false-positive cancer diagnosis results are mixed. Some studies have shown no effect of false positives on mental health. In a sample of individuals screened for colorectal cancer (n = 301), those with abnormal results (n = 165) had an increase in anxiety (STAI) and doubtfulness about the decision to be screened, which decreased over time.False-positive cancer screening results can increase symptoms of anxiety while patients are awaiting further examination. In a National Cancer Institute study , a subset of participants (n = 432) was screened annually for prostate, lung, colorectal, and ovarian cancer. Participants who received abnormal screening results reported worsening HRQL in the short term but not in the intermediate term. A number of studies on colorectal and ovarian cancer screening show that individuals reporting small but significantly higher symptoms of anxiety following a false-positive result subsided after being informed about the absence of cancer.,54,55 In a lung cancer screening study (n = 400), a small increase was found in anxiety symptoms (STAI) from baseline measures after indeterminate and suspicious results. However, anxiety symptoms returned to baseline scores 6 months after screening for those with suspicious results and 12 months for those with indeterminate results.Anxiety symptoms tended to decrease once false results were corrected. For example, in a breast cancer study (n = 285), a short-term increase in anxiety symptoms (HADS) was noted with false-positive screening results for breast cancer such that half (46%) of women experienced borderline to clinically significant anxiety symptoms while awaiting further examination, although the effect sizes were small. However, no difference was found at 3 and 12 months following the false-positive results compared with women with clear screening results. Women with false-positive screening results reported higher depressive symptom levels compared to women with normal screening results, initially after screening, a 1-week period between receiving the recall letter and attending the recall visit. However, false-positive females (n = 285) reported fewer depressive symptoms, based on the HADS, at 3 and 12 months following screening compared to females with normal screening results.Receiving false-positive results can increase depressive symptoms. In a study investigating the effects of breast cancer screening, females (n = 128) with false-positive results reported higher levels of depressive symptoms (HADS) at the follow-up appointment than at baseline. These increased levels of depressive symptoms were maintained at the 3- and 6-month follow ups. Depressive symptoms were also higher in the false-positive group than in those with normal results at 6-month follow up, although the effect sizes were small. Additional studies have replicated some of these results in women who received a false-positive result for ovarian cancer, finding that they showed increased cancer-related distress, which may reduce the likelihood of future screening. Similarly, a subset of the PLCO study (n = 432) found that participants who received abnormal results were less likely to adhere to procedures going forward than those who received normal results.Some evidence has been found regarding the long-term effects of false-positive results on mental health and behavior. A systematic review found that women who received false-positive mammography results were less likely to return for the next screening round. The authors concluded that the psychological impacts  of receiving a false-positive result can last up to 3 years.In summary, in most cases, false-positive cancer diagnoses have short-term negative mental health effects. In addition to negative mental health impacts, receiving false-positive results followed by corrected results can affect patient behavior. These behavioral changes should be considered alongside the benefits of cancer screening and delivery of results. Finally, consistent with the previous sections, the measures used in the above studies were not the gold standard for measuring anxiety and depressive symptoms. Better measures in larger samples must be employed to fully understand the effects of false-positive results. found that individuals with cancer reported more depressive symptoms than individuals in the general population, although the effect size was small. The prevalence of patients with a depressive disorder varies widely between individual studies (0–46%), which might be due to psychological health being differently impacted by the type of cancer.–62 Indeed, patients with lung, hematological, and gynecological cancers report the highest depressive symptom levels, and patients with skin and prostate cancers report the lowest depressive symptom levels, perhaps reflecting varying prognoses and treatments.Cancer diagnosis is a well-established risk factor for poor mental health. A meta-analysis of 58 studies–41 A meta-analysis of 25 studies revealed that 7% to 14% of cancer patients self-reported cancer-related PTSD symptoms. Furthermore, structured clinical interviews suggested that 13% of cancer patients had a lifetime prevalence of PTSD, with 6% currently having PTSD. Cancer stage had a significant effect on cancer-related PTSD rates. Rates were lower in patients with early stage (I–II) cancer to patients with advanced stage (III–IV) cancer, ranging from 4% to 12% and 11% to 31%, respectively. Those diagnosed at younger ages also had a greater risk of PTSD.Cancer can cause PTSD symptoms because of its life-threatening nature.Cancer diagnoses can also have long-term effects. One study (n = 1154) showed that 6 months after diagnosis, 22% of cancer patients reported symptoms indicating clinical levels of anxiety and 21% 1 year after diagnosis, 13% had clinical levels of depression, and 9% had both clinically significant anxiety and depression at both time points. One study (n = 5889) looking the 1 month prevalence of mental disorders in patients with cancer revealed that 32% had current psychological disorders. This study is 1 of the few to enlist diagnostic interviews and has a large sample size. Unfortunately, no baseline assessments were performed.Patients with clinical levels of anxiety are lowest in prostate cancer (8%), skin cancer (12%), and gastrointestinal cancer (17%), and highest in gynecological cancer (28%), lung cancer (26%), and head and neck cancer (24%). The most prevalent disorder in both groups was mood disorder, followed by anxiety disorder. Symptoms of depression were significantly associated with attitudes towards helplessness, hopelessness, fatigue, and a history of depression. These patterns of depression and anxiety have been replicated across studies and tend to peak in the short term after diagnosis and decrease over time.,67,68 In cases of higher and/or persistent depressive symptoms, women report a lower quality of life and worse recovery.In a breast cancer study, almost half of the women (n = 303) met the criteria for a psychiatric disorder.–74 In a large population-based study , patients with cancer had a 20% increased risk of suicide compared with the general population. Patients with pancreatic, mesothelioma, esophageal, and lung cancers are at the highest risk. A cohort study  investigating immediate suicides after a cancer diagnosis found that those with a cancer diagnosis were at an increased risk of dying by suicide within the first week postdiagnosis (12.6%) or year (3.1%) compared to those without a cancer diagnosis. Another study  found that suicide risk was the highest 2 months after multiple myeloma and acute myeloid leukemia diagnosis and was 3 times more frequent in male participants. These, and other findings in this section, call for increased psychological support for cancer patients, especially in the first 6 months after diagnosis. A meta-analysis on the impact of interventions on depression symptoms in cancer patients (n = 1362) found that targeted interventions can effectively decrease depression symptoms.The mental health impacts of cancer diagnosis can be more imminent and life threatening than the cancer itself, causing psychological distress that can lead to suicide.In summary, the results of studies on the psychological impact of receiving a cancer diagnosis can increase symptoms of anxiety and depression and can cause PTSD. Cancer diagnosis can have long-standing effects, likely due to the life-threatening nature of some malignancies. However, withholding a diagnosis of cancer is not ethical. Instead, the differential impacts of screening on mental health should be considered relative to the severity of the cancer being screened, and the benefits of sharing results when false positives are possible must be weighed.Taken together, literature on the mental health effects of cancer screening is limited Table . OverallTo fully understand the mental health effects of cancer screening, future studies must adopt a strategic and thorough approach. Studies should emphasize comprehensive psychological assessments using well-validated assessments at baseline, short-term, and longitudinal follow-up, comparing groups with and without screening, and within the screened group, with negative, positive, and false-positive results. Further, researchers should ensure that when negative psychological effects are present, the effect sizes are large enough to warrant information on best practices. Most of the available literature has only been cross-sectional, focused on short-term mental health effects, and lacks a longitudinal follow-up. Most studies only measured short-term distress (2 weeks before screening-1 month postscreening), underscoring the need for longitudinal studies. A more comprehensive assessment of mental health would provide a broader understanding of the role of cancer screening on functioning. Furthermore, differences across demographic features  must be explored. Integrating brief, easy-to-administer assessments into RCTs is a minimal investment for an exponential benefit. Having a thorough understanding of the mental health effects of cancer screening alongside physical and longevity gains will help us understand ethical screening types.There is a dearth of randomized controlled trials (RTCs) that specifically seek to answer the following question: what types of cancer screening are ethical? RCTs are needed to assess the effects of differential screening outcomes. Measures of mental health can easily be integrated into existing RCTs and studies investigating cancer progression. The field would benefit the most if RCTs employed common, validated measures of mental health and well-being. Indeed, a recent systematic review of the impact of cancer screening on mental health found that screening-associated distress was only detected in studies that used validated measures and was not detected using nonvalidated measures.,78,79 In-depth evidence on the mental health effects of cancer screening can help advocate for interventions, as research suggests that social and healthcare professional support can reduce anxiety levels.,45 Specifically, carefully designed RCTs are needed to fully evaluate when screening is justifiable to complete a half-painted picture. RCTs can be strengthened by integrating validated mental health measures at baseline and longitudinally across groups. Integrating measures of mental health into RCTs will provide a deeper understanding of the likely intricate and changing effects of cancer screening on mental health over time.In summary, there is evidence of both the negative and positive effects of cancer screening on mental health. The need for reliable cancer screening procedures to trigger early intervention is critical not only to add years to life, but also to life to years. However, the speed of cancer screening research has been fueled by the urgency to save lives. Despite the importance of improving survival rates, methodically rigorous studies are required to determine their beneficial and harmful effects. Benefits such as prolonged survival and positive mental health impacts need to outweigh the potential harm and health costs.Lauren: conception, primary writerInga: conception, secondary writerAndri: conception, editing, review, writing contributionsSigurdur: conception, editing, review, writing contributionsGudbjorg: editing, review, writing contributions


Centrosomes are best known as the microtubule organizing centers (MTOCs) of eukaryotic cells. In addition to their classic role in chromosome segregation, centrosomes play diverse roles unrelated to their MTOC activity during cell proliferation and quiescence. Metazoan centrosomes and their functional doppelgängers from lower eukaryotes, the spindle pole bodies (SPBs), act as important structural platforms that orchestrate signaling events essential for cell cycle progression, cellular responses to DNA damage, sensory reception and cell homeostasis. Here, we provide a critical overview of the unconventional and often overlooked roles of centrosomes/SPBs in the life cycle of eukaryotic cells. Ever since the centrosome was first discovered in the late 1800s, intense research efforts have been devoted to understanding its roles and life cycle in eukaryotic organisms. In their classic roles as microtubule-organizing centers (MTOCs), centrosomes and SPBs are classified amongst the most primitive organelles but gained complex ancillary functions throughout evolution . IncreasVisualized for the very first time through electron microscopy, SPBs were described as “small knobs” found at either ends of a long straight fiber during mitosis . SubsequBeyond MTOC activities, centrosomes/SPBs also promote cell signaling events induced by diverse stimulatory and stress signals. Here, we will review the non-canonical roles of MTOCs in cell homeostasis, with a specific focus on how the structural organization and subcellular position of centrosomes/SPBs play a central role in the modulation of cellular processes.α- and β-tubulin, centrosomes arrange and anchor microtubules that form the bipolar spindle in mitosis  were shown to asymmetrically divide by relying on the inheritance pattern of mother and daughter centrosomes through directional orientation of the mitotic spindle  axis. This rotation requires that one of the centrosomes, called the leading centrosome and chosen randomly, travels near the anterior border of the cell , existing at the distal end of mother centrioles across eukaryotic species except for nogaster , are reqnogaster . Subdistnogaster . Apart fnogaster . These snogaster . Centrionogaster .Analogous to centrosomes, SPBs of lower eukaryotes act as key microtubule organizing centers but differ dramatically in their mechanism-of-action and structural features . Across S. cerevisiae SPBs are tightly embedded in the nuclear membrane through three highly organized interconnected disk-like structures , central and inner (nuclear) layers. Despite these architectural differences, fission yeast SPBs nucleate both cytoplasmic and nuclear microtubules as budding yeast SPBs do and encompass a half bridge required for SPB duplication : Tub4/Gtb1; Spc97/Alp4; Spc98/Alp6; Spc110/Pcp1; Spc72/Mto1; Spc42/Ppc89; Cmd1/Cam1; Cnm67/Sid4; Nud1/Cdc11; Cdc31/Cdc31; Sfi1/Sfi1; Mps3/Sad1; Mps2/Kms2. For more details on S. pombe SPB and its structural intricacies, we direct readers towards the study of Fission yeast lication . Severali.e., the two centrioles present in each cell duplicate to generate two pairs where one template centriole is older than the newly generated copy; 1 phase start their assembly  and subdistal appendages (sDAPs). These appendages will evolve and mature until the G23 phase of the third cell cycle, after which the corresponding round of centriole assembly is complete , and embeds itself in the nuclear membrane only upon mitotic entry. In the literature, the timing of fission yeast SPB duplication throughout the cell cycle has been controversial for many years. Older studies state that SPB duplication occurs in G2/M  on the half-bridge, nuclear membrane invagination and gathering of material linking the premature SPB to the nuclear membrane. Akin to what is reported in budding yeast, the early event of SPB duplication giving rise to the lamellae bodies in fission yeast relies on the elongation of the half-bridge. The latter, without which SPB duplication could not take place, is required to support the development of the premature SPB. The newly created laminated structure, still undergoing maturation, remains linked to the mother SPB through an ellipsoid bridge  family, comprised of PLK1-PLK5 in humans, are serine/threonine kinases that regulate fundamental aspects of cell cycle progression . Within A damage . ImportaA damage .All PLKs share a C-terminal polo-box domain (PBD) and a highly conserved multi-domain structure with an N-terminal kinase domain (KD) that harbors a T-loop with an activating phosphorylation site . To recoThe other members of the PLK family perform distinct but sometimes overlapping functions in cell biology. PLK2, involved in centriole duplication, is dynamically expressed throughout the cell cycle and peaks at the G1/S transition of the cell cycle . Given iS. cerevisiae, Cdc5 decorates the nuclear surface of duplicating SPBs from late S phase to early anaphase and is also located in the nucleus. In late anaphase, Cdc5 enriches specifically on the cytoplasmic side of the parental SPB segregated to the daughter bud as well as on the bud neck  , composeApart from its involvement in mitotic entry, Plo1 is equally important throughout cell division. Plo1 shows two mechanistically distinct activity peaks during mitotic progression: First during prophase, where the formation of the actin ring occurs; second in late mitosis, corresponding to septum formation . Indeed,In human cells, the Aurora-A kinase, in complex with its co-factor Bora, phosphorylates Plk1 on a conserved residue located in the T-loop of its kinase domain (T210). This G2 phase phosphorylation event uniquely occurs at the centrosomes . ThroughThe dynamic localization of Cdc5/Plk1 at MTOCs has major implications for signal transduction events during the cellular response to DNA damage. Upon DNA damage, cells initiate a checkpoint response that allows time for DNA repair by preventing the G2/M transition . After sBRCA1 in mammary tissues can dysregulate centrosome duplication and generate a higher centriole number in vivo. This reported process requires the tethering of BRCA1 to centrosomes via RACK1. This protein also acts as a scaffolding factor that promotes Aurora A and PLK1 interaction in S phase. Previous literature linked RACK1 overexpression to centriole overduplication and involved BRCA1 as a component in this process   represento DDICA . It woulIn damaged cells, the generation of extra centrosomes can also be an outcome of circumstances unrelated to PLK1 or BRCA1 expression. Dodson and others notably reported that centrosome amplification can ensue an extended G2 phase caused by DNA damage checkpoint activation, in which DNA replication is paused but centrosome duplication remains. Interestingly, the small portion of cells able to override this G2/M cell cycle arrest were shown to contain a normal number of centrosomes . Other pCentrosome biogenesis is a process finely coordinated with other cell cycle cues to minimize errors during centriole duplication. In some cases, this control system fails despite its global efficacy and consequently leads to aberrations in centrosome biogenesis. In the literature, centrosome aberrations sometimes are described as a common outcome of neoplastic transformation . HoweverSimilarly to the PIDDosome signaling axis in response to centrosome amplification, another pathway termed the centrosome surveillance pathway monitors and reacts to centrosome loss or prolonged mitosis . In respRecent work has revealed that PKA activation is regulated differentially in distinct subcellular compartments, and that localized activation sites –known as signaling islands– are key in determining the profile of substrates modified by this kinase  family” for an overview of mitotic commitment in S. pombe) to spindle function, maintenance of nuclear envelope dynamics and regulation of the septum initiation network (SIN)  . Certainn humans . Despiteß-catenin, a multifunctional Wnt-pathway effector implicated in a wide array of biological contexts including centrosome-related cellular processes , a scaffold protein involved in both the canonical and non-canonical branches of the Wnt pathway. In higher organisms, three genes encode DVL isoforms –dundancy . The phodundancy . Nek2 cadundancy .http://www.cbioportal.org). Interestingly, the function of this centrosomal module was reported to be independent of centrosomes or microtubules and elegantly highlights how contextual Wnt signalling in cancer cells has the power to initiate processes such as cell migration as a means to augment metastatic potential.Apart from its implication in centrosome separation, the Wnt signaling pathway was also reported to play a role in cell motility. In response to exosome-transported signaling molecules named planar cell polarity (PCP) proteins, the Wnt pathway stimulates breast cancer cell (BCC) motility at the cell cortex. For this event to occur, the association of a centrosomal module is required. Specifically, DVL2 isoform was shown to mediate the assembly of this module, composed of the human centrosomal protein CEP192 and PLK4/AURKB, to promote protrusive activity in BCCs. This centrosomal module coordinates the exchange of formin DAAM1 for formin DAAM2 at the cell cortex, resulting in increased cell migration . This seDrosophila eye, the relationship between Nek2 and Wnt/Wingless is more direct. In a setting where the anaphase-promoting complex (APC) is inactivated, Nek2 accumulation causes hyperactivation of Wnt signaling and blocks retinal differentiation. Conversely, when Nek2 is degraded by APC, local Wnt signaling is suppressed and retinal differentiation proceeds (In the developing proceeds . Taken tThe mitotic exit network (MEN) is a GTPase signaling cascade that regulates cell cycle progression in budding yeast with similarities to the Hippo signaling pathway in metazoans. MEN drives the onset of mitotic exit in late anaphase and cytokinesis primarily by inhibiting the activity of Cdk1 and reversing phosphorylation sites on Cdk1 substrates. SPBs provide spatio-temporal cues for MEN, and importantly, functions as docking platforms to initiate and amplify signaling events.Up until anaphase, the GTPase Tem1, the main MEN initiator, is present at SPBs but is kept inactive until Cdc14 phosphatase is released from the nucleolus to create a positive feedback loop that drives the mitotic exit process  in fission yeast, a GTPase signaling cascade akin to the budding yeast MEN, regulates several mitotic processes occurring in the last steps of cell division. These processes include actomyosin ring constriction (CAR), septation and cytokinesis . The firdivision . Conversdivision .C. albicans or S. pombe thus lack this function of the MEN -signaling pathway only during the development of the Saccharomycetaceae family, other yeast species such as  the MEN . Moreove the MEN . The SPB the MEN . Importave trait . Despiteve trait . HoweverIn comparison to the vast body of knowledge collected on the MEN-SPBs relationship in budding yeast or the SIN-SPBs in fission yeast, the precise contribution of human centrosomes to mitotic exit remains relatively unexplored. The Hippo signaling pathway is an important regulator of cell proliferation and apoptosis in higher eukaryotes. Given its importance in chromosome segregation and cytokinesis, the Hippo pathway is thus considered to play a functionally analogous role to the MEN . AlthougThe studies discussed above describe how SPBs/centrosomes act as essential signaling centers for many biological processes. However, multiple lines of evidence reveal the existence of additional non-canonical roles for centrosomes/SPBs. In this section, we describe how nature and evolution co-opt MTOCs into fulfilling roles that go beyond their typical contribution to cell shape, intra-cellular transport and cell division. These roles require MTOC activity in some cases but utilize microtubules in ways that exceed and/or diverge from their primordial function in eukaryotic cells.When facing environmental stresses or severe nutrient deprivation, organisms ranging from bacteria and protozoa to plants and fungi can undergo sporulation as a way to adapt to environmental changes and increase the likelihood of their survival. Certain eukaryotic species, such as budding yeast, have the capacity to initiate sporulation as a form of specialized meiosis. This meiotic process allows for cells to shuffle and partition their genomic contents into different combinations, thus increasing the likelihood of progeny survival. In yeast, vegetative cells enter into premeiotic S phase. After completion of S phase, replicated DNA is partitioned into four haploid nuclei, which constitute the backbones of the four daughter cells to be created . This stSPBs support the initial construction of the prospore membrane, but the developmental reprogramming of vegetative cells that leads to sporulation alters their composition and function. During meiosis I, SPB duplication is similar to the process observed during mitotic division, but meiosis II induces multiple changes in SPB constitution that turns this organelle into a focal point for membrane formation. Most of its outer plaque components are replaced with specific proteins required for sporulation. During meiosis II, Mpc54, Spo74 and Spo21/Mpc70, three meiotic plaque components, act as substitutes for Spc72 on the cytoplasmic face of the SPBs. Instead of interacting with microtubules, Mpc54 and Spo21/Mpc70 cooperate with Nud1, Cnm67 and Spc42. The mechanistic process underpinning prospore membrane extension is not well understood, but we know that each prospore membrane surrounds its respective SPB in a semi-circular conformation prior to extension. Each membrane thus captures half of its corresponding nucleus, eventually forming walls englobing the entire nucleus . In theiEukaryotic cells rely heavily on stimuli provided by their immediate surroundings to make cell proliferation decisions. In situations where nutrients become limiting and proliferation is impossible, cells have the ability to initiate stress survival programs that enable them to better face environmental hazards. A cellular state termed quiescence can also be induced when nutrient become scarce or in the presence of specific developmental cues.Quiescence is a common dormant state in wildlife . Upon enEntry into quiescence induces major changes in cellular organization and physiology, including appearance of internal structures such as storage granules and actin bodies . The typAn important quiescence hallmark in yeast is the assembly of a long and highly stable array of nuclear microtubules (nMTs) which spans the entire length of the nucleus and consequently displaces the nucleolus . ChromosXRN1  encodes an exonuclease involved in nutrient signaling. Mutated xrn1 impaired relay of nutritional information to the SPBs, consistent with a possible role for the SPB as a signaling platform during quiescence  signaling in the early stages of quiescence, as suggested by Centrosomes and SPBs are cellular organelles mainly recognized for their role as microtubule nucleators (MTOCs) crucial for cell shape determination, intra-cellular transport and cell division. While there is little debate that this viewpoint is well justified, the importance of centrosomes/SPBs in other cellular processes must not be overlooked. Indeed, these organelles also act as key players in the transduction of several signalization events and in the implementation of important differentiation programs. Through their roles as intracellular docking platforms that enhance kinase-substrate interactions, centrosomes/SPBs effectively function as important STOCs. This role is achieved through the regulated formation of supramolecular protein assemblies on the surface of MTOCs. The scale and compositional complexities of these assemblies suggest that STOCs provide a unique regulatory environment for signaling events. Moreover, the dynamic nature of their location/movements during the cell cycle suggest a capacity for decoding and translating spatio-temporal cues into transduction events. Overall, centrosomes/SPBs are indispensable to ensure cellular fitness and mutations in these organelles can lead to severe pathologies, ranging from microcephaly to cancer . Given t


Traditionally, the presence of ductal carcinoma in situ (DCIS) with invasive breast cancer meant that the patient may require complete removal of the breast in order to completely remove the disease. Recently there has been some evidence to the contrary. In this article, we have reviewed the current published literature to determine the rate at which DCIS was eradicated by chemotherapy and endocrine therapies administered prior to surgery, which we determined to be 40.5% and 15% respectively. This suggests that in patient who respond well to pre-surgical systemic therapy, breast conserving surgery (BCS) could be offered. This should lessen patient anxiety and morbidity.Contrary to traditional assumptions, recent evidence suggests that neoadjuvant systemic therapy (NST) given for invasive breast cancer may eradicate co-existent ductal carcinoma in-situ (DCIS), which may facilitate de-escalation of breast resections. The aim of this systematic review was to assess the eradication rate of DCIS by NST given for invasive breast cancer. Searches were performed in MEDLINE using appropriate search terms. Six studies (N = 659) in which pathological data were available regarding the presence of DCIS prior to neoadjuvant chemotherapy (NACT) were identified. Only one study investigating the impact of neoadjuvant endocrine therapy (NET) met the search criteria. After pooled analysis, post-NACT pathology showed no residual DCIS in 40.5% of patients . There was no significant difference in DCIS eradication rate between triple negative breast cancer (TNBC) and HER2-positive disease (45% vs. 46% respectively). NET achieved eradication of DCIS in 15% of patients (9/59). Importantly, residual widespread micro-calcifications after NST did not necessarily indicate residual disease. In view of the results of the pooled analysis, the presence of extensive DCIS prior to NST should not mandate mastectomy and de-escalation to breast conserving surgery (BCS) should be considered in patients identified by contrast enhanced magnetic resonance imaging (CE-MRI). One of the enduring challenges in the surgical management of invasive breast cancer (IBC) is the adverse impact of co-existing extra-tumoral ductal carcinoma in-situ (DCIS) on decision making. In particular, the indication for therapeutic mastectomy is frequently driven by the extent and distribution of associated non-invasive disease. The proportion of tumours with an in situ component adjacent to IBC ranges from 33%  to 53% . ResectiAnother pertinent issue related to co-existent DCIS with invasive ductal carcinoma (IDC) [IDC-DCIS] is the interpretation of residual DCIS with regard to the response status of patients after neoadjuvant systemic treatment (NST). This issue affects a significant subset of patients. In a retrospective survey of 20,495 cases, Ploumen et al. reported the persistence of DCIS in 4.3% of patients after neoadjuvant therapy for IBC (ypTis) [Since DCIS is a non-invasive disease where cells possess physiological mechanisms affording protection from cytotoxic drugs in a manner similar to normal cells, it has been historically assumed that this precludes response to systemic chemotherapy or targeted therapy . HoweverFor the purposes of this systematic review, MEDLINE and The United States National Library of Medicine (NLM) database of the biomedical literature were searched using the PubMed engine and the following terms: ‘DCIS and chemotherapy’, ‘DCIS and endocrine therapy’, ‘DCIS trastuzumab’, ‘DCIS pertuzumab’, ‘DCIS neoadjuvant chemotherapy’, ‘DCIS neoadjuvant systemic therapy’, and ‘DCIS neoadjuvant endocrine therapy’.The eligibility criteria of the systematic review were as follows: (1) Patients diagnosed with breast cancer undergoing neoadjuvant systemic therapy including chemotherapy, anti-HER2 therapy, checkpoint inhibitors or endocrine therapy, (2) Pathological data regarding the presence of DCIS before and after NST were available, (3) Prospective, retrospective and randomised controlled trials (RCTs), (4) Language restrictions in English, and (5) Sample size of the study was more than 50 cases.Exclusion criteria included the following: (1) Abstracts, case reports and lectures, (2) Preoperative systemic therapy prescribed for short duration (less than 4 weeks) to assess change of biomarkers, (3) Incorrect or incomplete data that were unable to be extracted from other relevant studies, (4) Duplicate publications. Articles that met the criteria were retrieved for full-text evaluation and the relevant patient level data extracted and compiled for down-stream analysis. Subsequent pooled and subgroup analyses were performed to reflect the principal clinical phenotypes of disease.Chi-square test was used to compare the eradication rate between HER2 positive triple negative breast cancer subgroups, and between NET and NACT. Yate’s correction was also used to correct the error introduced by assuming that the discrete probabilities of frequencies in the table can be approximated by a continuous distribution.p-value of 0.05 was accepted as the threshold of statistical significance.A The literature search identified 1412 articles pertaining to NACT, of which six studies satisfied the aforementioned inclusion and exclusion criteria. These studies encompassed 659 patients in which pathological data regarding the presence of DCIS before and after NACT were available, detailed in Pooled analysis of the data showed that DCIS was eradicated by NACT in 267 of 659 patients, yielding a rate of 40.5% (95% CI: 36.8–44.3). In these cases, the final post-NST histology confirmed no residual DCIS, where pre-NST biopsy showed adjacent or intra-tumoral DCIS. Notably, the rate of eradication was highest (50.8%) in those with HER2-positive disease, particularly when the DCIS was also HER2-positive . Among tp = 0.003), NET could nonetheless achieve eradication of DCIS in some cases.There were 332 articles identified regarding NET, of which only one  satisfieSubgroup analyses were performed reflecting the principal clinical phenotypes of disease receiving NST.p = 0.00003) and TNBC treated with NACT , compared to ER-positive DCIS treated with NET. This suggests that NET is less effective in eradicating DCIS than regimens containing chemotherapy with or without targeted anti HER2 antibodies.The DCIS eradication rate was significantly greater in HER2-positive disease . Although the study may have lacked sufficient power to identify small differences, large variations between these subsets would be expected to show.Interestingly, there was no statistically significant difference identified when directly comparing HER2-positive and TNBC . This observation may be attributed to the biology of the tumour or more likely to the use of targeted biological therapy consisting of monoclonal antibodies against HER2 rather than chemotherapy. Although there was limited data regarding the effect of NST on DCIS associated with TNBC, the rate of eradication observed was comparable to HER2-positive disease , again significantly higher than ER-positive disease. The recent advent of checkpoint inhibitors, increasingly used in the neoadjuvant setting for TNBC >2cm, is likely to further increase the eradication rate of co-existing DCIS [This systematic review of the literature, followed by pooled and subset analyses, clearly demonstrates that contrary to historical assumptions, DCIS can respond favourably to NST and be completely eradicated in a significant proportion of cases. Underpinning the frequency and extent of response appears to be the tumour biology of DCIS. The susceptibility of non-invasive disease to NST is predicted to some extent by the immuno-phenotype, approximating the intrinsic molecular subtype. Overexpression of HER2 was associated with a higher incidence of co-existing DCIS  and a hiing DCIS . This coThis systematic review has several notable limitations. Firstly, the studies included were mostly retrospective and employed heterogeneous pathology protocols. Secondly some of the studies included intra-tumoral DCIS, the biology of which could differ from adjacent DCIS. Thirdly, the absence of DCIS in post-NST histology may reflect the in-situ component being entirely removed during diagnostic biopsy, rather than any impact of NST on DCIS. Fourthly, it is very likely that the presence of DCIS before commencing NST was underestimated, thus leading to underestimation of the response rate . FifthlyThe presence of extensive DCIS in association with invasive breast cancer is often considered to be an absolute indication for mastectomy, even for patients receiving NST. This dogma is based on the widely held assumption that DCIS does not respond well to NST. However, the data presented in this study demonstrate that 40% of DCIS can be eradicated by NST. There is now compelling evidence to challenge this paradigm and breast conserving surgery (BCS) should be the preferred option for excellent responders. This selected group of patients can be identified by post-NST contrast-enhanced MRI, demonstrating the impact of NST on previously enhancing non-invasive disease. The accumulating evidence that BCS with radiotherapy is associated with better overall survival than mastectomy alone, further strengthens the argument for conservative surgery wherever possible ,15. In aThe literature search identified only one study pertaining to DCIS eradication in response to NET. A single arm phase II clinical trial investigated the impact of neoadjuvant letrozole on pure ER-positive DCIS. After six months of treatment, the authors observed an eradication rate of 15%, significantly lower than that observed for NST that includes chemotherapy and targeted therapy for invasive breast cancer associated with DCIS . ExtensiThere is a growing body of evidence that residual DCIS alone  does not adversely impact overall survival ,17. OsdoRecent studies have demonstrated that in triple negative DCIS, tumour infiltrating lymphocytes express high levels of PD-L1 (>50% cells), indicating potential susceptibility to PD-L1 antagonists . In patiThe potential role of liquid biopsy using circulating tumour DNA or circulating tumour cells platforms should be investigated in future studies as a tool of assessment of completeness of resection .Based on this systematic review of the literature and subtype-specific analysis, it is reasonable for individual tumour boards to consider de-escalation of breast surgery in carefully selected patients with extensive co-existent DCIS showing excellent response to NST especially in patients with HER2 positive and triple negative breast cancer.We propose that such patients undergo breast CE-MRI surveillance for two years following BCS in addition to standard annual mammographic screening. Areas of abnormal enhancement on MRI or change in the microcalcifications would represent an indication for imaging guided tissue sampling This personalised approach, particularly in the context of HER2-positive and triple-negative breast cancer, can potentially spare patients the physical and psychological morbidity of unnecessary mastectomy.


Obesity is a growing health problem that affects both children and adults. The increasing prevalence of childhood obesity is associated with comorbidities such as cardiovascular disease, type 2 diabetes and metabolic syndrome due to chronic low-grade inflammation present at early stages of the disease. In pediatric patients suffering from obesity, the role of epigenetics, the gut microbiome and intrauterine environment have emerged as causative factors Interestingly, pediatric obesity is strongly associated with low birth weight. Accelerated weight gain oftentimes occurs in these individuals during the post-natal period, which can lead to increased risk of adiposity and metabolic disease. The pathophysiology of obesity is complex and involves biological and physiological factors compounded by societal factors such as family and community. On a cellular level, adipocytes contained within adipose tissue become dysregulated and further contribute to development of comorbidities similar to those present in adults with obesity. This review provides an overview of the current understanding of adipose tissue immune, inflammatory and metabolic adaptation of the adipose tissue in obesity. Early cellular changes as well as the role of immune cells and inflammation on the progression of disease in pivotal pediatric clinical trials, adult studies and mouse models are emphasized. Understanding the initial molecular and cellular changes that occur during obesity can facilitate new and improved treatments aimed at early intervention and subsequent prevention of adulthood comorbidities. IGFBP-1), which plays a role in the development of metabolic disease [IGFBP-1 lead to insulin resistance and potentially type 2 diabetes [Obesity is a global health epidemic that affects both children and adults. Obese children are more likely to become obese adults  and it i disease . Studiesdiabetes . HoweverChildhood obesity persists as a serious public health problem. Effective obesity prevention strategies and policies exist in children and adolescents; however, as reported in different clinical trials their positive effects are short-lived . What isA systematic search of the literature was performed on studies published between January 2000 and July 2022. The following keywords were used to search for relevant papers associated with childhood/adolescent obesity such as: childhood obesity or pediatric obesity; obesity-related inflammation; obesity-related endocrine system complications, obesity-related immune system, pathogenesis of low chronic inflammatory state within the adipose tissue, ectopic lipid accumulation; adipose tissue-associated inflammation; pro-inflammatory responses; dietary patterns; nutrients. The following electronic databases were searched: PubMed, EMBASE and Web of Science lastaccess on 30 of July 2022. The contributions were collected and analyzed, and the resulting data was assembled to provide a comprehensive review.Adipose tissue is a secretory organ capable of releasing endocrine hormones, cytokines, exosomes, miRNA, lipids, and peptide hormones that can act in a paracrine and autocrine manner. Adipose tissue can be categorized into three different cell types: white (WAT), brown (BAT), and beige (or brite) adipose tissue. White adipose tissue stores energy while BAT usually assists in maintenance of body temperature due to its high metabolic activity and high concentration of mitochondria. Additionally, it also contributes to energy expenditure. Brite adipose tissue is found scattered within the WAT and regulates the response to cold adaptation or other stimuli . White aFABP4), glutathione peroxidase 3 (GPX3) and CD36 molecule, which are involved in fatty acid handling machinery [Adipose tissue is composed of endothelial cells, mesenchymal stem cells, fibroblasts, pre-adipocytes, macrophages and several types of immune cells  located achinery . Single achinery ,39. Addiachinery ,40. Scavachinery . It has achinery . When elThe conformational changes of adipocytes and the cells contained within the SVF during obesity that contribute to development of comorbidities is an area of ongoing investigation. In general, the three main functions of the adipocyte within the white adipose tissue  are lipid storage, secretory function and insulin sensitivity. Disruption of these essential functions during obesity has profound systemic effects . AdiposeIt is well known that obesity leads to a chronic inflammatory state and associated pathophysiological sequelae such as insulin resistance, altered lipid metabolism and ectopic lipid deposition B. Normal2 correlated with higher production of MCP-1 and C-reactive protein (CRP) levels [The hypoxic environment created within adipocytes (excessive hyperplasia and/or hypertrophy) during an obese state has negative downstream effects that modulate the inflammatory response in both visceral and subcutaneous depots. One such response is the increased recruitment of monocytes and subsequent macrophage production. The primary immune response lead by macrophages involves pattern recognition receptors (PRRs) which include toll like receptors (TLRs). Toll like receptor 4 (TLR4) initiates saturated fatty acid mediated macrophage inflammation . Obesity) levels . In a co) levels . Other f) levels . These sAdipose tissue macrophages (ATMs) are pivotal players in obesity associated inflammation and metabolic disease . The twoAdditionally, macrophages are capable of secreting chemotactic molecules such as tumor necrosis factor α (TNF-α) . TNF-α hAdditionally, TNF-α, IL-6 and MCP-1 have been observed in the serum of individuals with diabetes and elevated production of TNF-α leads to increased serum glucose concentrations ,69. In aRecent studies report that immune cells such as neutrophils, mast cells, and eosinophils, infiltrate adipose tissue and lead to chronic inflammation . In the 2 demonstrated normalized NK cell functionality within 6 months post-surgery [Eosinophils serve as a negative regulator of adipose tissue inflammation. They are present in the SVF of lean adipose tissue and produce IL-4, a driver of the M2 anti-inflammatory pathway. In obese mice, the concentration of eosinophils is diminished, resulting in the loss of this protective pathway . Further-surgery . UnderstIn addition to innate immune cells, T cell and B cell activation during the adaptive immune response also plays a large role in the regulation of adipose tissue inflammation. Several studies have demonstrated that these cells reside within the adipose tissue and regulate inflammation ,84. CD4+Additionally, studies in preclinical models of obesity demonstrate that B cells play a critical role in adipose tissue inflammation since they infiltrate visceral adipose tissue in response to high fat diets. Mice fed a high fat diet also demonstrated early accumulation of immune cells and increased T cell numbers, which correlated with the incidence of insulin resistance and macrophage accumulation in adipose tissue . In miceAdipose tissue is a highly dynamic organ and is capable of responding to environmental inputs with hypertrophy (for lipid storage) or hyperplasia. Alterations in the tissue occur within days of an obesogenic diet . MaladapThe decreased capacity of adipocytes to continue to store and retain triglycerides in obesity, causes ectopic fat accumulation in liver and muscle leading to insulin resistance, which is considered the key mediator in cardio metabolic disease . EmerginThe sympathetic nervous system is also implicated in the mobilization of fatty acids from white adipose tissue. Ganglionic sympathetic nerves innervate adipocytes . NorepinAdipocyte cell size has also been found to have an impact on glucose and lipid metabolism. In morbidly obese women, mean visceral and subcutaneous fat cell sizes were found to be related to in vivo markers of inflammation, glucose metabolism and lipid metabolism. These associations were independent of age, BMI or body fat distribution .MMP9), when compared with eight lean children. MMP9 is a family of zinc-dependent endopeptidases that interact with components of basement membranes and extracellular matrix This upregulation led to hypertrophy and hyperplasia of adipocytes [In childhood obesity, cells within the SVF including macrophages, NK cells, B cells and T cells are dysregulated . Long-teipocytes . Adiposeipocytes .Children suffering from obesity (ages 6–17 years of age), have lower levels of NK cells in peripheral blood when compared to lean children at the same age. This affects the ability of their immune system to destroy infected cells or initiate inflammatory cascades against abnormal cells as previously described . In a moInterestingly, exercise is an effective mitigation strategy in preventing metabolic disease in children. Increased physical activity leads to improvement in adipocyte expansion in the visceral and subcutaneous tissue . Animal Peripheral blood cells (PBC) can reflect the inflammatory profiles of internal tissues. This is important as adipose tissue collection from pediatric populations is challenging without surgical intervention. A cross sectional analysis of inflammatory markers such as CRP, neutrophil count and ferritin/transferrin ratio in children ages 1 to 17 years old was completed. CRP levels of >1.0 mg/L were evident among children with obesity as early as 3 years old. In children 6 to 8 years of age, an abnormal neutrophil count was noted among children with severe obesity and an increased prevalence of abnormal ferritin/transferrin ratio began at 9 to 11 years of age, demonstrating how early obesity increases inflammation . Leptin,Obesity is associated with a chronic inflammatory state that is present in the pediatric population. The effects of obesity in pediatric patients can be long lasting, even with a normalized BMI by adulthood . Adipose


Three-year follow-up CT imaging shows no evidence of tumor recurrence.A 64-year-old patient presented with shortness of breath and chest pressure. The initial examination was unremarkable, and a chest X-ray revealed a large mediastinal mass. Computed tomography (CT) scan demonstrated a lobulated mediastinal mass involving the great vessels and mass effect on the trachea, esophagus, and heart. A CT-guided biopsy showed a monotonous, evenly spaced population of mature, normal-appearing adipocytes consistent with a well-differentiated lipoma-like liposarcoma/atypical lipomatous tumor. The patient underwent a median sternotomy with  Mediastinal liposarcomas are rare and comprise less than 1% of all mediastinal tumors. The majority are found either in the lower extremities or the retroperitoneum . AMediastinal masses can present with various symptoms, including dyspnea, arrhythmias, and dysphagia. These masses usually have an insidious growth course and only become symptomatic once they exert a mass effect on local structures . They arLiposarcoma of the mediastinum with simultaneous involvement of anterior and posterior compartments is a rare entity that has seldom been described in the literature. The majority of currently described treatment algorithms involve peripherally involved tumors; however, when they are found in the mediastinum, the standard of care is elusive. Reviewing a compilation of the literature helps design the optimal treatment algorithm. Primary surgical resection may be curative for mediastinal liposarcomas, and locally advanced tumors may benefit from neoadjuvant chemoradiation . This caThis report documents a liposarcoma of the mediastinum that achieved a favorable surgical treatment outcome, albeit not without complications involving injury to surrounding structures. The lack of a standard of care for the treatment of this rare tumor necessitates the use of similar case reports and series to supplement clinical decision-making in designing optimal treatment strategies. Despite the involvement of major peri-mediastinal structures, aggressive en bloc resection may be considered in cases without distant metastasis and with anticipation and surgical management of possible resulting complications.