ANCA negative pulmonary vasculitis: a challenging diagnosis.

A man in his 40s with end-stage kidney disease due to IgA nephropathy and receiving peritoneal dialysis presented with a 1-week history of breathlessness, cough and nosebleeds. CT scan of the chest revealed ground glass changes while blood tests indicated elevated inflammatory markers and a negative vasculitis screen. This included negative ANCA and anti-GBM antibodies. Initial treatment for suspected atypical pneumonia with antibiotics yielded no clinical improvement.Over the course of the admission, his symptoms progressively worsened, leading to oxygen dependency with a FiO2 of 40% and episodes of haemoptysis. Suspicions of pulmonary vasculitis arose due to clinical deterioration, prompting consultation with a tertiary vasculitis centre. It was subsequently concluded that the clinical and radiological findings correlated with ANCA-negative pulmonary vasculitis or a rare case of IgA-associated pulmonary capillaritis. Treatment with methylprednisolone and rituximab led to significant improvement, allowing rapid oxygen withdrawal. The patient was discharged with a tapering prednisolone regimen.

Loss of the BRCA1-PALB2 interaction accelerates p53-associated tumor development in mice.

The BRCA1-PALB2-BRCA2 axis, or the BRCA pathway, plays key roles in genome stability maintenance and suppression of breast and several other cancers. Due to frequent p53 mutations in human BRCA1 breast cancers and mouse mammary tumors from Brca1, Brca2 and Palb2 conditional knockout models, it is often thought that p53 inactivation accelerates BRCA1/2 and PALB2-associated tumorigenesis. Here, we studied tumor development in mice with a mutation in Palb2 that disengages the PALB2-BRCA1 interaction in different Trp53 backgrounds. Rather than mammary tumors, Palb2 and Trp53 compound mutant mice developed, with greatly reduced latencies, lymphomas and sarcomas that are typically associated with germline Trp53 inactivation. Whole exome sequencing failed to identify any significant differences in genomic features between the same tumor types of Trp53 single mutant and Palb2;Trp53 compound mutant mice. These results suggest that loss of the BRCA pathway accelerates p53-associated tumor development, possibly without altering the fundamental tumorigenic processes.

Tumor suppressor PALB2 maintains redox and mitochondrial homeostasis in the brain and cooperates with ATG7/autophagy to suppress neurodegeneration.

The PALB2 tumor suppressor plays key roles in DNA repair and has been implicated in redox homeostasis. Autophagy maintains mitochondrial quality, mitigates oxidative stress and suppresses neurodegeneration. Here we show that Palb2 deletion in the mouse brain leads to mild motor deficits and that co-deletion of Palb2 with the essential autophagy gene Atg7 accelerates and exacerbates neurodegeneration induced by ATG7 loss. Palb2 deletion leads to elevated DNA damage, oxidative stress and mitochondrial markers, especially in Purkinje cells, and co-deletion of Palb2 and Atg7 results in accelerated Purkinje cell loss. Further analyses suggest that the accelerated Purkinje cell loss and severe neurodegeneration in the double deletion mice are due to excessive oxidative stress and mitochondrial dysfunction, rather than DNA damage, and partially dependent on p53 activity. Our studies uncover a role of PALB2 in mitochondrial homeostasis and a cooperation between PALB2 and ATG7/autophagy in maintaining redox and mitochondrial homeostasis essential for neuronal survival.

Genetic interactions among Brca1, Brca2, Palb2, and Trp53 in mammary tumor development.

Inherited mutations in BRCA1, BRCA2, and PALB2 cause a high risk of breast cancer. Here, we conducted parallel conditional knockout (CKO) of Brca1, Palb2, and Brca2, individually and in combination, along with one copy of Trp53, in the mammary gland of nulliparous female mice. We observed a functional equivalence of the three genes in their basic tumor-suppressive activity, a linear epistasis of Palb2 and Brca2, but complementary roles of Brca1 and Palb2 in mammary tumor suppression, as combined ablation of either Palb2 or Brca2 with Brca1 led to delayed tumor formation. Whole-exome sequencing (WES) revealed both similarities and differences between Brca1 and Palb2 or Brca2 null tumors. Analyses of mouse mammary glands and cultured human cells showed that combined loss of BRCA1 and PALB2 led to high levels of reactive oxygen species (ROS) and increased apoptosis, implicating oxidative stress in the delayed tumor development in Brca1;Palb2 double CKO mice. The functional complementarity between BRCA1 and PALB2/BRCA2 and the role of ROS in tumorigenesis require further investigation.

Influence of vitamin C on irradiated mice tissues induced DNA double strand breaks DSB using gH2AX marker.

OBJECTIVE: To investigate the modifying effect of treatment with vitamins C on irradiated mice tissues with gamma ray. METHODS: The animal experimental study was conducted in the Iraqi Centre for Cancer Research and Medical Genetics (ICCMG), Unit of Medical Physics department of Physiology college of Medicine/ Al_Mustansiryah Baghdad, Iraq from December 2019 to April 2020 Comprised adult male Albino Bulb /c mice aged 8 weeks. They were randomly divided into 4 equal groups. Group 1, the controls, received standard saline solution untreated and were not exposed to radiation. Group 2 mice received dose of vitamin C 200mg/kg/day intra-peritoneally injected without radiation. Group 3 was exposed to gamma ray without treatment with vitamin C. Group 4 mice were administrated vitamin C 200mg/kg/day intraperitoneally and exposed to the gamma ray. Groups 3 and 4 received 4 Gy of gamma rays for eight consecutive days. All groups were sacrificed by cervical dislocation at 1, 3 and 24h. Post-radiation testes and spleen tissues were collected. Damage in vivo was measured by gamma H2AX foci as biomarker of deoxyribonucleic acid double strand breaks in testes and spleen tissues. Data was analsyed using SPSS 24. RESULTS: There were 28 mice with a mean bodyweight of 20±2g; 7(25%) in each of the four groups. There was significant difference (p<0.05) between group 4 and group 3 in terms of foci forming. Significant differences (p<0.05) were found between the exposed and unexposed groups. CONCLUSIONS: Vitamin C was found to be a good radio-protective agent for mice testes and spleen tissues. The main differences were clearly observed in the formation of gamma H2AX foci between testes and spleen due to their sensitivity to ionising radiation which depends on proliferation activity.

Re-validate the dataset of Iraq cancer registries.

OBJECTIVE: To evaluate the cancer registry in Iraq over a 5 year period from 2013 to 2018 (except 2017 as software data was not accessable) in all of Iraqi's provinces. Further more to study the incidence rate and the pattern of distribution of breast cancer in various provinces of Iraq. METHODS: All data was collected from the cancer registration centres of Iraq. Original data is set to highlight and update the cancer state of the country. RESULTS: On data analysis it was observed that the incidence of cancer with the number of new cases each year, were higher in some cities compared to others. The major cause for this difference is the displacement of people from their home cities due to ISIS attack, which changed the demographic distribution of people in Iraq. Current results revealed an increase in the number of new cases registered annually during 1994-2018. Moreover, cancer incidence rate per 1005 population showed that Baghdad, Karbala and Al Najaf have a higher incidence in the period between 2013-2018. Breast cancer in females is the most frequent malignancy in Iraq, followed by colon cancer and leukaemia. This reveals the importance of cancer awareness programmes in drawing the attention to early diagnosis and treatment. CONCLUSIONS: This study provides the incidence of cancer, especially breast cancer in Iraq. This will assist the researchers to identify regional differences in the prevalence figures.

Parathyroid gland weight is associated with high density lipoprotein levels in patients with primary hyperparathyroidism.

OBJECTIVE: To investigate the relationship between parathyroid gland weight and high-density lipoprotein (HDL) levels in patients with primary hyperparathyroidism (PHPT). METHODS: In this retrospective case control study, we reviewed 329 PHPT patients aged from 20 to 85 years who had a parathyroidectomy at Robert Wood Johnson University Hospital. The patients were divided into 5 quintiles according to their parathyroid gland weight: 68 patients had a parathyroid gland weight <0.3 g, 66 patients had a gland weight 0.3-0.45 g, 67 patients had a gland weight 0.45-0.7 g, 63 patients had a gland weight 0.7-1.25 g, and 65 patients had a gland weight ≥1.25 g. RESULTS: Body Mass Index (BMI) trended to be higher across the quintiles of parathyroid gland weight (P = 0.003). Serum calcium and PTH levels were significantly increased across parathyroid gland quintiles (p < 0.0001). HDL levels tended to be lower across the increasing quintiles of parathyroid gland weight (P = 0.01). There was a negative relationship between log parathyroid gland weight and HDL in patients with PHPT in a simple linear regression (r = -0.160, P = 0.003). The negative association remained significant after adjustment for age and BMI (r = -0.114, P = 0.039). Furthermore, parathyroid gland weight was significantly associated with levels of triglyceride (r = 0.126, P = 0.02), but this relationship lost its significance after adjustment for age and BMI (r = 0.082, P Ëƒ 0.05). CONCLUSIONS: PHPT patients with heavier parathyroid glands tended to have higher BMI and lower HDL levels.

How can we make renal medicine careers more appealing to UK trainees?

BACKGROUND: There is a global decline in interest in careers in renal medicine. This is concerning given the increasing global burden of kidney disease. Previous studies in the USA and Australia have identified factors such as a poor work-life balance, lack of role models and the challenging nature of the speciality as possible reasons behind recruitment struggles. This study aimed to identify factors associated with declining interest among trainees in the UK. METHODS: We conducted a survey of 150 National Health Service Foundation trainees (interns) and Core Medical Trainees in Health Education West Midlands. Participants completed a 14-part paper-based questionnaire capturing data on trainee demographics, medical school and postgraduate exposure to renal medicine and perceptions of a career in renal medicine. RESULTS: There was limited early clinical exposure to renal medicine both in terms of time spent in the speciality and perceived exposure to the range of domains of the speciality. Trainees perceived the speciality as complex with a heavy workload. Very few trainees considered the speciality to be lifestyle oriented. There was also disinterest in taking on the associated general medicine commitments of the training programme. Job experience and identification of role models increased the likelihood of consideration of the speciality. CONCLUSION: This survey has identified key areas to drive interest in the speciality, including early engagement, enthusiastic supervision and increased training flexibility. Urgent attention is required to address these areas and make renal medicine careers more appealing.

Evidence of Intertissue Differences in the DNA Damage Response and the Pro-oncogenic Role of NF-κB in Mice with Disengaged BRCA1-PALB2 Interaction.

The BRCA1-PALB2-BRCA2 axis plays an essential role in DNA homologous recombination repair, defect in which drives genome instability and cancer development. How cells with defects in this pathway respond to DNA damage in vivo and how tumors develop from these cells remain poorly defined. Here, we analyzed several aspects of the DNA damage response in multiple tissues of Palb2-mutant mice in which the interaction between PALB2 and BRCA1 is disengaged. Without any challenge, the mutant mice showed increased endogenous DNA damage. Following ionizing radiation, the mutant mice displayed higher levels of DNA breaks and stronger induction of p53 and p21, but continued DNA synthesis, reduced apoptosis, and accelerated tumor development. The differences in p21 induction, DNA synthesis, and apoptosis between wild-type and mutant mice were substantially more pronounced in the mammary gland than in the intestine, suggesting a potential contributing factor to the increased risk and the tissue specificity of BRCA/PALB2-associated tumor development. Moreover, the mutant mice showed higher levels of reactive oxygen species and constitutive activation of NF-κB, an antiapoptotic transcription factor inducible by both DNA damage and oxidative stress. Treatment of the mutant mice with an inhibitor of NF-κB reactivated apoptosis and delayed tumor development following radiation. Thus, our results also suggest a prosurvival and pro-oncogenic role of NF-κB in PALB2-mutant cells.Significance: This study explores novel tumor suppression mechanisms of the BRCA1-PALB2 DNA damage response pathway and implicates NF-κB activation as a protumorogenic event and possible therapeutic target. Cancer Res; 78(14); 3969-81. ©2018 AACR.

NRF2 Induction Supporting Breast Cancer Cell Survival Is Enabled by Oxidative Stress-Induced DPP3-KEAP1 Interaction.

NRF2 is a transcription factor serving as a master regulator of the expression of many genes involved in cellular responses to oxidative and other stresses. In the absence of stress, NRF2 is constantly synthesized but maintained at low levels as it is targeted by KEAP1 for ubiquitination and proteasome-mediated degradation. NRF2 binds KEAP1 mainly through a conserved "ETGE" motif that has also been found in several other proteins, such as DPP3, which has been shown to bind KEAP1 and enhance NRF2 function upon overexpression. Here we demonstrate the interaction between endogenous DPP3 and endogenous KEAP1. We further show that the DPP3-KEAP1 interaction is strongly induced by hydrogen peroxide and that DPP3 is required for timely NRF2 induction and nuclear accumulation in the estrogen receptor (ER)-positive MCF7 breast cancer cells. Moreover, we present evidence that the binding of DPP3 to KEAP1 stabilizes the latter. Finally, we show that DPP3 is overexpressed in breast cancer and that elevated levels of DPP3 mRNA correlate with increased NRF2 downstream gene expression and poor prognosis, particularly for ER-positive breast cancer. Our studies reveal novel insights into the regulation of NRF2 and identify DPP3 and an NRF2 transcriptional signature as potential biomarkers for breast cancer prognosis and treatment. Cancer Res; 77(11); 2881-92. ©2017 AACR.