Complementary interhelical interactions between three buried Glu-Lys pairs within three heptad repeats are essential for Hec1-Nuf2 heterodimerization and mitotic progression.

Hec1 and Nuf2, core components of the NDC80 complex, are essential for kinetochore-microtubule attachment and chromosome segregation. It has been shown that both Hec1 and Nuf2 utilize their coiled-coil domains to form a functional dimer; however, details of the consequential significance and structural requirements to form the dimerization interface have yet to be elucidated. Here, we showed that Hec1 required three contiguous heptad repeats from Leu-324 to Leu-352, but not the entire first coiled-coil domain, to ensure overall stability of the NDC80 complex through direct interaction with Nuf2. Substituting the hydrophobic core residues, Leu-331, Val-338, and Ile-345, of Hec1 with alanine completely eliminated Nuf2 binding and blocked mitotic progression. Moreover, unlike most coiled-coil proteins, where the buried positions are composed of hydrophobic residues, Hec1 possessed an unusual distribution of glutamic acid residues, Glu-334, Glu-341, and Glu-348, buried within the interior dimerization interface, which complement with three Nuf2 lysine residues: Lys-227, Lys-234, and Lys-241. Substituting these corresponding residues with alanine diminished the binding affinity between Hec1 and Nuf2, compromised NDC80 complex formation, and adversely affected mitotic progression. Taken together, these findings demonstrated that three buried glutamic acid-lysine pairs, in concert with hydrophobic interactions of core residues, provide the major specificity and stability requirements for Hec1-Nuf2 dimerization and NDC80 complex formation.

Key factors for establishing and sustaining a successful palliative radiation oncology program: a survey of the Society for Palliative Radiation Oncology.

BACKGROUND: Dedicated palliative radiation oncology programs (PROPs) within radiation oncology (RO) practices have been shown to improve quality and decrease costs of radiation therapy (RT) in advanced cancer patients. Despite this, relatively few PROPs currently exist, highlighting an unmet need to understand characteristics of the few existing PROPs and the potential barriers and facilitators that exist in starting and maintaining a successful PROP. We sought to assess the attributes of existing PROPs, the facilitators and barriers to establishing these programs, and the resources needed to create and maintain a successful program. METHODS: A 15-item online survey was sent to 157 members of the Society of Palliative Radiation Oncology (SPRO) in July 2019. RESULTS: Of the 157 members, 48 (31%) responded. Most practiced in an academic center (71% at main center and 15% at satellite) and 75% were from a larger group practice (≥6 physicians). Most (89%) believed the development and growth of a dedicated PROPs was either important (50%) or most important (39%) to the field of RO. Only 36% of respondents had a PROP, 38% wanted to establish one, and 13% were currently developing one. Of those with PROPs (N=16), 75% perceived an increase in the number of referrals for palliative RT since starting the program. A majority had an ability to refer to an outside palliative care specialist (64%), an outpatient RO service (53%), and specialized clinical processes for managing palliative radiotherapy patients (53%), with 41% having an inpatient RO consult service. Resources considered most essential were access to specialist-level palliative care, advanced practice provider support, a radiation oncologist with an interest in palliative care, having an outpatient palliative RO clinic, an emphasis on administering short radiation courses, and opportunities for educational development. Of those with a PROP or those who have tried to start one, the greatest perceived barriers to initiating a PROP were committed resources (83%), blocked out clinical time (61%), challenges coordinating management of patients (61%), and support from leaders/colleagues (61%). Perceived barriers to sustaining a PROP were similar. For those without a PROP, the perceived most important resources for starting one included access to palliative care specialist by referral (83%), published guidelines with best practices (80%), educational materials for referring physicians and patients (80%), educational sessions for clinical staff (83%), and standardized clinical pathways (80%). CONCLUSIONS: PROPs are not widespread, exist mainly within academic centers, are outpatient, have access to palliative care specialists by referral, and have specialized clinical processes for palliative radiation patients. Lack of committed resources was the single most important perceived barrier for initiating or maintaining a PROP. Best practice guidelines, educational resources, access to palliative care specialists and standardized pathways are most important for those who wish to develop a PROP. These insights can inform discussions and help align resources to develop, grow, and maintain a successful PROP.

Systematic review of brachytherapy for symptom palliation.

PURPOSE: Brachytherapy is most often applied in the curative or salvage setting, but many forms of brachytherapy can be helpful for symptom palliation. Declining utilization is seen, for multiple reasons, such as lack of awareness, insufficient expertise, or poor access to equipment. High level evidence for many types of palliative brachytherapy has been lacking. The objective of the current study was to review the evidence for utilization and efficacy of brachytherapy to palliate symptoms from cancer. MATERIALS AND METHODS: We performed a systematic search in EMBASE and MEDLINE for English-language articles published from January 1980 to May 2022 that described brachytherapy used for a palliative indication in adults with a diagnosis of cancer (any subtype) and at least one symptom related outcome. Individual case reports and conference abstracts were excluded. All publications were independently screened by two investigators for eligibility. RESULTS: The initial search identified 3637 abstracts of which 129 were selected for in-depth review. The number of studies (total number of patients) included in the final analysis varied widely by tumor site with the majority (68.2%) involving either lung or esophageal cancer. Despite a limited number of prospective trials that assessed the efficacy of brachytherapy for symptom management, there was a positive effect on palliation of symptoms across all tumor types. There was no clear trend in the number of publications over time. The most commonly cited symptom indications for palliation by brachytherapy were dysphagia, dyspnea, pain and bleeding. CONCLUSIONS: Brachytherapy can provide palliation for patients with advanced cancer, across different tumor sites and clinical scenarios. However, high level evidence in the literature to support palliative applications of brachytherapy is lacking or limited for many tumor sites. There appears to be a strong publication bias towards positive studies in favor of brachytherapy. Beyond anecdotal reports and individual practices, outcomes research can further our understanding of the role of brachytherapy in palliating advanced cancers of all types, and should be encouraged.

Mutation of NIMA-related kinase 1 (NEK1) leads to chromosome instability.

BACKGROUND: NEK1, the first mammalian ortholog of the fungal protein kinase never-in-mitosis A (NIMA), is involved early in the DNA damage sensing/repair pathway. A defect in DNA repair in NEK1-deficient cells is suggested by persistence of DNA double strand breaks after low dose ionizing radiation (IR). NEK1-deficient cells also fail to activate the checkpoint kinases CHK1 and CHK2, and fail to arrest properly at G1/S or G2/M-phase checkpoints after DNA damage. RESULTS: We show here that NEK1-deficient cells suffer major errors in mitotic chromosome segregation and cytokinesis, and become aneuploid. These NEK1-deficient cells transform, acquire the ability to grow in anchorage-independent conditions, and form tumors when injected into syngeneic mice. Genomic instability is also manifest in NEK1 +/- mice, which late in life develop lymphomas with a much higher incidence than wild type littermates. CONCLUSION: NEK1 is required for the maintenance of genome stability by acting at multiple junctures, including control of chromosome stability.

Radiation oncology resident education in palliative care.

Palliative and supportive care education for radiation oncologists in training is essential to deliver comprehensive care to patients. Surveys on palliative care education among radiation oncology program directors and residents demonstrate a disparity in formal teaching and didactics. Integration of formal didactics, communications skills programs, and teaching modules are being piloted at academic centers. A dedicated palliative radiation oncology service has been implemented and the experience evaluated. Future directions to improve resident education in palliative care include improving access and time dedicated to formal didactics, online and interactive modules, rotation in a palliative care service, emphasis on board examinations, and consideration of an advanced palliative care fellowship for radiation oncologists. This is the first review of the available literature reviewing formal palliative education in radiation oncology training programs in the United States.

A targeted needs assessment to improve referral patterns for palliative radiation therapy.

Radiation therapy (RT) can effectively palliate a variety of symptoms in patients with metastatic cancer, using relatively low doses that infrequently cause major side effects. However, palliative radiation is often underutilized and sub-optimally implemented. In this study, we surveyed the Society of Palliative Radiation Oncology (SPRO) membership to identify barriers to appropriate referral for palliative RT that they encounter in their practice, and identify specific groups of physicians who radiation oncologists believed would benefit most from further education on when to refer patients. A total of 28 radiation oncologists responded to the survey with a response rate of 20.5%. On average, participants felt that referrals for palliative RT were inappropriately delayed 46.5% [standard deviation (STD) 20.2%] of the time. The most common barrier to referral for medical oncologists was thought to be potential interference with systemic therapy (33%); for primary care physicians and surgeons it was a lack of knowledge about the benefit (42%), and for palliative care physicians it was concern for patient convenience (25%). For brain metastases and spinal cord compression radiation oncology was felt to be part of the initial referral sequence more than 50% of the time, but less so for thoracic airway obstruction/bleeding (38%), esophageal obstruction (16%), or urinary obstruction/bleeding (8%), where another subspecialist was more often consulted first. Primary care, geriatric medicine, and emergency medicine were considered among the least knowledgeable specialties about palliative radiation. These hypothesis-generating findings can guide approaches to improve referral patterns for this important aspect of supportive care.

Nondestructive imaging of live human keloid and facial tissue using multiphoton microscopy.

OBJECTIVES: To use multiphoton microscopy to image collagen fibers and matrix structure in nonfixed human keloid tissue and normal human facial skin obtained following surgery and to compare the findings to existing knowledge of normal skin and keloid morphology to determine if this technology is a suitable adjunct for conventional histology. METHODS: Epidermis was removed to expose the fibroblast-rich dermal layer that was then imaged using a multiphoton confocal microscope (Zeiss-Meta 510; Carl Zeiss, Jena, Germany). An 800-nm tunable titanium/sapphire femtosecond laser (Mai-Tai; Newport Co Spectra-Physics, Mountain View, California) was used to excite the tissue; second harmonic generation between 397 and 408 nm and autofluorescent signals were collected. Images were obtained using a Plan-Neofluar x40 oil immersion objective lens and a Plan-Apochromat x63 oil immersion lens. RESULTS: Compared with normal skin, keloids showed disorganized collagen fibers arranged in complex swirls and bundles 20 to 30 microm in diameter. Normal tissue showed collagen fibers as distinct, straight strands less than 10 microm in diameter. Differences between normal and keloid tissue were subtle but apparent. CONCLUSIONS: The value of imaging living tissue is a significant benefit. Because keloids and hypertrophic scars result from altered collagen metabolism, the development of clinical multiphoton microscopy systems may allow examination of wound healing dynamics in vivo and potentially provides a means to monitor therapy without the need for biopsy or the risk of injury to tissue.

Top 10 Tips Palliative Care Clinicians Should Know About Radiation Oncology.

As palliative care (PC) moves upstream in the course of advanced illness, it is critical that PC providers have a broad understanding of curative and palliative treatments for serious diseases. Possessing a working knowledge of radiation therapy (RT), one of the three pillars of cancer care, is crucial to PC providers given RT's role in both the curative and palliative settings. This article provides PC providers with a primer on the vocabulary of RT; the team of people involved in the planning of RT; and common indications, benefits, and side effects of treatment.

Palliative radiotherapy for skin malignancies.

Palliative radiotherapy (PRT) improves patient quality of life (QoL) through alleviating cancer-associated symptoms such as pain, bleeding, and ulceration. Palliative management of patients with skin malignancies requires consideration of cosmetic and psychosocial outcomes as QoL measures. In this review, we highlight the current literature and advances in the use of PRT for patients with the three most commonly encountered forms of skin malignancies: basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and melanoma. The disease course and sensitivity to radiation varies, thus dictating the palliative goal and scheduling for PRT.

Palliative care and palliative radiation therapy education in radiation oncology: A survey of US radiation oncology program directors.

PURPOSE: The purpose of this study was to assess the state of palliative and supportive care (PSC) and palliative radiation therapy (RT) educational curricula in radiation oncology residency programs in the United States. METHODS AND MATERIALS: We surveyed 87 program directors of radiation oncology residency programs in the United States between September 2015 and November 2015. An electronic survey on PSC and palliative RT education during residency was sent to all program directors. The survey consisted of questions on (1) perceived relevance of PSC and palliative RT to radiation oncology training, (2) formal didactic sessions on domains of PSC and palliative RT, (3) effective teaching formats for PSC and palliative RT education, and (4) perceived barriers for integrating PSC and palliative RT into the residency curriculum. RESULTS: A total of 57 responses (63%) was received. Most program directors agreed or strongly agreed that PSC (93%) and palliative radiation therapy (99%) are important competencies for radiation oncology residents and fellows; however, only 67% of residency programs had formal educational activities in principles and practice of PSC. Most programs had 1 or more hours of formal didactics on management of pain (67%), management of neuropathic pain (65%), and management of nausea and vomiting (63%); however, only 35%, 33%, and 30% had dedicated lectures on initial management of fatigue, assessing role of spirituality, and discussing advance care directives, respectively. Last, 85% of programs reported having a formal curriculum on palliative RT. Programs were most likely to have education on palliative radiation to brain, bone, and spine, but less likely on visceral, or skin, metastasis. CONCLUSIONS: Residency program directors believe that PSC and palliative RT are important competencies for their trainees and support increasing education in these 2 educational domains. Many residency programs have structured curricula on PSC and palliative radiation education, but room for improvement exists in management of fatigue, assessing role of spirituality, and discussion regarding advance care planning.

Attitudes of radiation oncologists toward palliative and supportive care in the United States: Report on national membership survey by the American Society for Radiation Oncology (ASTRO).

PURPOSE: Radiation oncologists are frequently involved in providing palliative and supportive care (PSC) for patients with advanced cancers through delivery of palliative radiation. Whether they are confident in their ability to assess and initiate treatments for pain, nonpain, and psychosocial distress is unknown. The American Society for Radiation Oncology surveyed its practicing members in the United States on self-assessment of their primary PSC skills and access to continuing medical education on PSC. METHODS: We electronically surveyed 4093 practicing radiation oncologists in the United States. The survey consisted of 16-questions in 5 sections1: demographics,2 PSC training,3 domains of PSC,4 perceived barriers as a radiation oncologist to initiate advanced care planning, and5 discussion of prognosis. RESULTS: The survey was e-mailed to 4093 American Society for Radiation Oncology members, and 649 responses were received (response rate 16%). The majority (91%) of radiation oncologists surveyed believe PSC is an important competency for radiation oncologists. Most radiation oncologists reported that they are moderately confident in their ability to assess and manage pain and gastrointestinal symptoms, but less confident in their ability to manage anorexia, anxiety, and depression. Despite areas of decreased confidence, a large number (42%) of radiation oncologists do not receive any additional PSC education beyond their residency training. Lastly, a perceived fear of upsetting referring medical oncologists and lack of clinic time are concerns for radiation oncologists who may want to initiate goals of care/advance care planning discussions with patients and their families. CONCLUSION: Radiation oncologists are more confident in their ability to assess and manage pain than in their ability to manage depression, anxiety, anorexia, and fatigue. There is a need for increasing continuing medical educational efforts in PSC for practicing radiation oncologists, and strengthening PSC training in residency programs.

Radiation oncology resident palliative education.

PURPOSE: Although palliative care is recognized as integral to oncology care, limited data exist regarding the extent to which palliative care training is incorporated into radiation oncology residency training in the United States. We aim to characterize US radiation oncology residents' perceived palliative care educational needs and experience to guide future palliative oncology educational interventions. METHODS AND MATERIALS: An 8-person expert panel developed a survey to assess resident perceptions of generalist palliative care education within radiation oncology residency. Domains of palliative oncology education, derived from national guidelines, included symptom management (pain and non-pain), communication about goals of care, advance care planning, psychosocial issues, cultural considerations, spiritual needs, care coordination, and ethical/legal issues. Residents rated adequacy of their training and their perceived competency in each domain. A total of 433 US radiation oncology residents were identified for participation; 404 completed the survey (response rate, 93%). RESULTS: Residents characterized themselves as "not at all/minimally/somewhat confident" in their ability to take care of patients with palliative care issues in the following domains: symptom management (36% pain, 44% non-pain), communication about goals of care (31%), advance care planning (48%), psychosocial (55%), cultural (22%), spiritual (44%), care coordination (50%), and ethical/legal (50%). On average, 79% of residents rated their training as "not/minimally/somewhat" adequate across all domains. Most (96%) view palliative care as an important competency within radiation oncology and 81% desire more palliative care education. CONCLUSIONS: Although the majority of residents view palliative care as an important competency for radiation oncologists, a majority perceived their educational training as inadequate across multiple domains. Most residents desire further palliative oncology care training. These findings suggest efforts should be made to improve palliative care education during radiation oncology training.

Focal Hepatic Fluorodeoxyglucose Uptake Mimics Liver Metastasis Following External Beam Radiation for Gastroesophageal Cancers: A Case and Review of the Literature.

Patients with locally advanced gastroesophageal cancers frequently undergo concurrent chemotherapy and radiation (CRT). 18-fluorodeoxyglucose-positron emission tomography ((18)FDG-PET) in combination with computed tomography is used for disease staging and assessing response to therapy. (18)FDG-PET interpretation is subject to confounding influences including infectious/inflammatory conditions, serum glucose, and concurrent medications. Radiotherapy induces tissue damage, which may be associated with FDG-avidity; however, few reports have described the focal areas of hepatic uptake following concurrent chemoradiation (CRT). Distinguishing hepatic FDG uptake from disease progression represents an important clinical scenario. Here, we present two cases of unexpected FDG uptake in the liver after CRT and review the literature describing incidental liver uptake on FDG-PET.

Radiation dermatitis caused by a bolus effect from an abdominal compression device.

American Association of Physicists in Medicine (AAPM) Task Group 176 evaluated the dosimetric effects caused by couch tops and immobilization devices. The report analyzed the extensive physics-based literature on couch tops, stereotactic body radiation therapy (SBRT) frames, and body immobilization bags, while noting the scarcity of clinical reports of skin toxicity because of external devices. Here, we present a clinical case report of grade 1 abdominal skin toxicity owing to an abdominal compression device. We discuss the dosimetric implications of the utilized treatment plan as well as post hoc alternative plans and quantify differences in attenuation and skin dose/build-up between the device, a lower-density alternative device, and an open field. The description of the case includes a 66-year-old male with HER2 amplified poorly differentiated distal esophageal adenocarcinoma treated with neoadjuvant chemo-radiation and the use of an abdominal compression device. Radiation was delivered using volumetric modulated arc therapy (VMAT) with 2 arcs using abdominal compression and image guidance. The total dose was 50.4Gy delivered over 40 elapsed days. With 2 fractions remaining, the patient developed dermatitis in the area of the compression device. The original treatment plan did not include a contour of the device. Alternative post hoc treatment plans were generated, one to contour the device and a second with anterior avoidance. In conclusion, replanning with the device contoured revealed the bolus effect. The skin dose increased from 27 to 36Gy. planned target volume (PTV) coverage at 45Gy was reduced to 76.5% from 95.8%. The second VMAT treatment plan with an anterior avoidance sector and more oblique beam angles maintained PTV coverage and spared the anterior wall, however at the expense of substantially increased dose to lung. This case report provides an important reminder of the bolus effect from external devices such as abdominal compression. Special consideration must be given to contour and/or avoiding beam entrance to the device, and to the use of such devices in patients who may have heightened radiosensitivity, such as those who are human immunodeficiency virus (HIV)-positive.

Bone mineral density loss in thoracic and lumbar vertebrae following radiation for abdominal cancers.

PURPOSE: To investigate the relationship between abdominal chemoradiation (CRT) for locally advanced cancers and bone mineral density (BMD) reduction in the vertebral spine. MATERIALS AND METHODS: Data from 272 patients who underwent abdominal radiation therapy from January 1997 to May 2015 were retrospectively reviewed. Forty-two patients received computed tomography (CT) scans of the abdomen prior to initiation and at least twice after radiation therapy. Bone attenuation (in Hounsfield unit) (HU) measurements were collected for each vertebral level from T7 to L5 using sagittal CT images. Radiation point dose was obtained at each mid-vertebral body from the radiation treatment plan. Percent change in bone attenuation (Δ%HU) between baseline and post-radiation therapy were computed for each vertebral body. The Δ%HU was compared against radiation dose using Pearson's linear correlation. RESULTS: Abdominal radiotherapy caused significant reduction in vertebral BMD as measured by HU. Patients who received only chemotherapy did not show changes in their BMD in this study. The Δ%HU was significantly correlated with the radiation point dose to the vertebral body (R=-0.472, P<0.001) within 4-8 months following RT. The same relationship persisted in subsequent follow up scans 9 months following RT (R=-0.578, P<0.001). Based on the result of linear regression, 5 Gy, 15 Gy, 25 Gy, 35 Gy, and 45 Gy caused 21.7%, 31.1%, 40.5%, 49.9%, and 59.3% decrease in HU following RT, respectively. Our generalized linear model showed that pre-RT HU had a positive effect (ß=0.830) on determining post-RT HU, while number of months post RT (ß=-0.213) and radiation point dose (ß=-1.475) had a negative effect. A comparison of the predicted versus actual HU showed significant correlation (R=0.883, P<0.001) with the slope of the best linear fit=0.81. Our model's predicted HU were within ±20 HU of the actual value in 53% of cases, 70% of the predictions were within ±30 HU, 81% were within ±40 HU, and 90% were within ±50 HU of the actual post-RT HU. Four of 42 patients were found to have vertebral body compression fractures in the field of radiation. CONCLUSIONS: Patients who receive abdominal chemoradiation develop significant BMD loss in the thoracic and lumbar vertebrae. Treatment-related BMD loss may contribute to the development of vertebral compression fractures. A predictive model for post-CRT BMD changes may inform bone protective strategies in patients planned for abdominal CRT.

The dosimetric impact of image guided radiation therapy by intratumoral fiducial markers.

PURPOSE: Pancreatic fiducials have proven superior over other isocenter localization surrogates, including anatomical landmarks and intratumoral or adjacent stents. The more clinically relevant dosimetric impact of image guided radiation therapy (IGRT) using intratumoral fiducial markers versus bony anatomy has not yet been described and is therefore the focus of the current study. METHODS AND MATERIALS: Using daily orthogonal kV or cone beam computed tomography (CBCT) images and positional and dosimetric data were analyzed for 12 consecutive patients treated with fiducial based IGRT and volumetric modulated arc therapy to the intact pancreas. The shifts from fiducial to bone (ΔFid-Bone) required to realign the daily fiducial-matched pretreatment images (kV, CBCTs) to the planning computed tomography (CT) using bony anatomic landmarks were recorded. The isocenter was then shifted by (ΔFid-Bone) for 5 evenly spaced treatments, and the dosimetric impact of ΔFid-Bone was calculated for planning target volume coverage (PTV50.4 and PTV47.9) and organs at risk (liver, kidney, and stomach/duodenum). RESULTS: The ΔFid-Bone were greatest in the superoinferior direction (ΔFid-Bone anteroposterior, 2.7 ± 3.0; left-right, 2.8 ± 2.8; superoinferior, 6.3 ± 7.9 mm; mean ± standard deviation; P = .03). PTV50.4 coverage was reduced by 13% (fiducial plan 95 ± 2.0 vs bone plan 82 ± 12%; P = .005; range, 5%-52%; >5% loss in all; and >10% loss in 42% of patients), and to a lesser degree for PTV47.9 (difference, -8%; range, 1%-30%; fiducial plan 100 ± 0.3% vs bone plan 92 ± 7.6%; P = .003; with reductions of >5% in 66% and >10% in 33% of patients). The dosimetric impact of ΔFid-Bone on the organs at risk was not significant. Positional shifts for kV- and CBCT-based realignments were nearly identical. CONCLUSION: Compared with matching by fiducial markers, IGRT matched by bony anatomy substantially reduces the PTV50.4 and PTV47.9 coverage, supporting the use of intratumoral pancreatic markers for improved targeting in IGRT for pancreatic cancer.

Immunohistochemical detection of telomerase reverse transcriptase in colorectal adenocarcinoma and benign colonic mucosa.

Telomerase activity (TA) is increased in human cancers and cell lines and is thought to contribute to their immortality. High TA has been found to correlate with aggressive tumor behavior. The aim of this study was to determine whether increased TA in colorectal carcinoma (CRC) correlates with survival. Formalin-fixed and paraffin-embedded tissue sections from 82 CRC and 6 cases of benign colon with diverticulosis were immunohistochemically stained for telomerase reverse transcriptase (TRT) using the immunoperoxidase method. The percentage of positive nuclei was determined for each case. Survival analysis was performed using the Kaplan-Meier method. TRT immunoreactivity was always nuclear. In normal colonic mucosa, TRT immunoreactivity was detected in the bottom of crypts. However, in normal colon adjacent to CRC, telomerase immunoreactivity was detected throughout the length of the crypts, including the upper third, and frequently in the surface epithelium. Telomerase immunoreactivity in more than 25% of the cancer cell nuclei was associated with significantly poorer patient survival (P = 0.0081). We conclude that increased TA in CRC, as demonstrated by TRT immunostaining, is associated with poorer survival, and that TA is present in normal colonic mucosa and is increased in colonic mucosa near CRC. Additional studies with larger patient samples and multivariate analysis are needed to determine whether TRT expression is an independent prognostic factor in CRC.

Increased Nek1 expression in renal cell carcinoma cells is associated with decreased sensitivity to DNA-damaging treatment.

Renal cell carcinoma (RCC) is a heterogeneous disease with resistance to systemic chemotherapy. Elevated expression of multiple drug resistance (MDR) has been suggested to be one of the mechanisms for this resistance. Here, we provide an alternative mechanism to explain RCC's resistance to chemotherapy-induced apoptosis. Never-in mitosis A-related protein kinase 1 (Nek1) plays an important role in DNA damage response and proper checkpoint activation. The association of Nek1 with the voltage-dependent anion channel (VDAC1) is a critical determinant of cell survival following DNA-damaging treatment. We report here that Nek1 is highly expressed in RCC tumor and cultured RCC cells compared to that of normal renal tubular epithelial cells (RTE). The association between Nek1 and VDAC1 is genotoxic dependent: prolonged Nek1/VDAC1 dissociation will lead to VDAC1 dephosphorylation and initiate apoptosis. Down-regulation of Nek1 expression in RCC cells enhanced their sensitivity to DNA-damaging treatment. Collectively, these results suggest that the increased Nek1 expression in RCC cells maintain persistent VDAC1 phosphorylation, closing its channel and preventing the onset of apoptosis under genotoxic insults. Based on these results, we believe that Nek1 can serve as a potential therapeutic target for drug development in the treatment of RCC.

Polyglandular autoimmune syndrome disguised as mental illness.

Our case acts to highlight the numerous presentations of polyglandular autoimmune syndromes. A 62-year-old Taiwanese woman with a history of schizophrenia presented to our emergency department with a brain tumour causing her headaches. She was admitted due to severe anaemia, and after further investigation, the patient was discovered to have pernicious anaemia and autoimmune thyroiditis-consistent with the diagnosis of polyglandular autoimmune syndrome IIIb. Her underlying primary psychiatric diagnosis was then questioned. The diagnosis of her endocrinopathies were likely delayed for many years due to the psychiatric disorder which may have been due to her long-standing autoimmune hypothyroidism and/or vitamin B12 deficiency. Initial treatment brought about major behavioural improvement, and encourages physicians to investigate secondary causes of psychosis and other coexisting autoimmune diseases when a patient presents with one endocrinopathy.